Lossen rearrangement
Chemical rearrangement reaction
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Through Carboxylic acid, Amine and Alcohol (chemistry)
Reaction mechanism
The acyl hydroxamate is first converted to its conjugate base. A concerted rearrangement event then occurs in which the amide substituent migrates to the amide nitrogen. This displaces the carboxylic acid the nitrogen donates a pair of electrons to form the isocyanate C=N double bond, and the N–O σ-bond breaks. The rate of the rearrangement shows a strong dependence on the pKa of the carboxylic acid leaving group, with electron withdrawing groups giving faster rates.
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Synthetic Applications
The Lossen rearrangement is an alternative to the Curtius, Hofmann and Schmidt rearrangements which avoids the use of explosive reagents like azides or oxidants like bromine. In the context of organic synthesis, the Lossen rearrangement starts with activation of a hydroxamic acid by an electrophile. The acyl hydroxamate is typically not isolated. Acid chlorides and anhydrides are the most commonly used. An example of the use of acetic anhyrdride comes from the synthesis of an aminopyrimidone intermediate in the synthesis of human neutrophil elastase inhibitor.
The scope of electrophilic activators has expanded to include altermatives such as sulfonyl chlorides as well as CDI. The use of CDI has been demonstrated at large scale in the synthesis of a glucosylceramide synthase (GCS) inhibitor.
In the presence of acetonitrile, which can act as an electrophile to form an amidine intermediate, addition of a strong Brønsted base is sufficient to promote the Lossen rearrangement. This “self-propagating” Lossen rearrangement highlights that the isocyanate can serve as an electrophilic activator for the hydroxamic acid. This was demonstrated at large scale in the synthesis of a HIV inhibitor.
Historical references
- Lossen, W. (1872). "Ueber Benzoylderivate des Hydroxylamins". Justus Liebigs Annalen der Chemie. 161 (2–3): 347–362. doi:10.1002/jlac.18721610219.
- Lossen, W. (1875). "Ueber die Structurformel des Hydroxylamins und seiner amidartigen Derivate". Justus Liebigs Annalen der Chemie. 175 (3): 271–304. doi:10.1002/jlac.18751750303.
- Lossen, W. (1875). "Methode, die Carboxylgruppe aromatischer Säuren durch die Amidgruppe zu ersetzen". Justus Liebigs Annalen der Chemie. 175 (3): 313–325. doi:10.1002/jlac.18751750305.