What Is Hofmann rearrangement?
The Hofmann rearrangement reaction refers to the rearrangement of primary amides under the action of sodium hypobromite (produced by the reaction of sodium hydroxide and bromine water) to form primary amines with one less carbon. This reaction, characterized by its unique rearrangement step, offers a powerful method for amine synthesis, chain shortening, and accessing valuable synthetic intermediates.
- Reagents: Halogen source (typically bromine).
- Reactants: Primary carboxamides.
- Products: Primary amines.
- Reaction Type: Rearrangement reaction.
- Related Reactions: Curtius rearrangement, Lossen rearrangement, Schmidt reaction, Wolff rearrangement.
Experimental tips:
- The R group can be an alkyl or aryl group. When R is an alkyl group with more than 6 carbons, the yield is low. At this time, Br2/NaOMe can be used instead of Br2/NaOH, and the product is an amino acid ester (RNHCOOMe), which can be hydrolyzed to an amine.
- The oxidative rearrangement of primary amides can also be oxidized by other oxidants. Sodium hypochlorite and lead tetraacetate are often used as alternative oxidants. The use of high-valent iodine as a relatively green reagent can avoid the use of toxic reagents such as bromine and lead.
- NBS/DBU is a mild system and methoxy, amino, and nitro-substituted benzamides can also react smoothly.
Fig 1. Hofmann rearrangement and its mechanism. [1]
Mechanism of Hofmann Rearrangement
Like the Curtius rearrangement, the Lossen rearrangement and the Schmidt reaction, the Hofann rearrangement is a 1,2-nucleophilic rearrangement (migration) reaction with isocyanates as intermediates. The latter are rarely isolated, but are directly formed into the product primary amines through hydrolysis and decarboxylation. If the isocyanate is alcoholyzed, it will give carbamates, and if the amine is hydrolyzed, it will give ureas. In these reactions, if the migrated carbon is a chiral carbon, the configuration is maintained.
The following are typical reaction steps:
- N-Halogenation: The primary amide is rapidly halogenated at the nitrogen atom to form the N-bromoamide.
- Deprotonation: The weakly acidic N-H proton of the N-bromoamide is abstracted by the base, to generate the conjugate base, an N-bromoamide anion. This anion is relatively stable at low temperatures.
- Migration: On warming, the N-bromoamide anion then undergoes a concerted 1,2-shift. In this step, the R group migrates from the carbonyl carbon to the adjacent nitrogen atom. This occurs with simultaneous loss of the bromide ion. The product of this rearrangement is the isocyanate.
- Hydrolysis: The highly electrophilic isocyanate intermediate is rapidly attacked by water/alcohol. This hydrolysis occurs via nucleophilic addition to the electrophilic carbon of the isocyanate, to form an unstable carbamic acid.
- Decarboxylation: The carbamic acid spontaneously loses carbon dioxide, to give the final primary amine product.
Application Examples of Hofmann Rearrangement
- Example 1: Zong Chang et al. described a method for incorporating amine and carboxylic acid functional groups into the diastereoisomer azabicyclo[3.2.0]heptanedione (compound 3c). The process involved sequential selective hydrolysis, Hofmann rearrangement, and amine protection, resulting in the racemic N,O-diprotected 3-HACBC, (±)-5, with an 81% yield. [2]
- Example 2: Sébastien Daver et al. developed a kilogram-scale synthetic route for the production of a novel topical antiandrogen ((S)-N-(2-bromo-6-methoxypyridin-4-yl)-2-hydroxy-2,4-dimethylpentanamide) starting from citric acid. The Hofmann rearrangement is the key step in the synthesis of the aminopyridine intermediate. [3]
Fig 2. Synthetic examples via Hofmann rearrangement.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 256-258.
- Chang, Zong, et al. The Journal of Organic Chemistry, 2018, 83(1), 527-534.
- Daver, Sébastien, et al. Organic Process Research & Development, 2017, 21(2), 231-240.
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