What Is Lossen rearrangement?
Lossen rearrangement is the base-induced thermal rearrangement of O-acylated hydroxamic acids (or activated hydroxamic acid derivatives) to isocyanates. The isocyanate, which can be isolated, is then hydrolyzed to give a primary amine with one fewer carbon atom than the starting hydroxamic acid. The reaction is one of several classical methods for converting carboxylic acids (R-COOH) to primary amines (R- NH2), together with the Hofmann, Curtius and Schmidt rearrangements. The reaction is named for the German chemist Wilhelm Lossen, who first reported the transformation in 1872.
Lossen rearrangement reactions starting directly from hydroxamic acid, although conceptually straightforward, are rarely used because of the difficulty in preparing hydroxamic acid, its limited stability, and the potential for self-condensation side reactions. Solving the problem of self-condensation of hydroxamic acid has been done in two ways: one is to use activated hydroxamic acid. The other is to improve the group's migration ability. For example, with the help of the excellent migration ability of phosphinyl group, phosphinyl hydroxamic acid can undergo spontaneous Lossen rearrangement.
- Reagents:
a) Activators: Acyl chlorides (e.g., AcCl, BzCl), carboxylic anhydrides (e.g., Ac2O), dialkyl dicarbonates (e.g., Boc2O, CICO2Et), carbodiimides (e.g., DCC).
b) Base: Required for deprotonation (e.g., NaOH, KOH, Et3N, pyridine, DBU).
c) Reactants: Activated hydroxamic acid derivatives or hydroxamic acids. - Products: Isocyanates; primary amines/carbamates (urethanes)/substituted ureas.
- Reaction Type: Rearrangement reaction.
- Related Reactions: Curtius rearrangement, Hofmann rearrangement, Schmidt reaction, Wolff rearrangement.
Experimental Tips:
- Certain hydroxamic acids bearing good leaving groups directly on the oxygen (e.g., sulfonyl esters like tosylates) can undergo direct Lossen rearrangement without prior O-acylation.
- Migration aptitude favors tertiary > secondary > primary alkyl. Methyl and some primary alkyl groups migrate poorly.
Fig 1. Lossen rearrangement and its mechanism. [1]
Mechanism of Lossen Rearrangement
The Lossen rearrangement mechanism parallels that of the Hofmann rearrangement. It involves three key stages: 1) Activation: Hydroxamic acids require initial conversion to an O-acyl derivative. 2) Deprotonation and Rearrangement: Base treatment of the activated species removes the acidic N-H proton, forming an anion. This anion undergoes a concerted intramolecular [1,3]-sigmatropic rearrangement where the R group migrates from the carbonyl carbon to the neighboring nitrogen atom while expelling a carboxylate anion, yielding an electrophilic isocyanate. 3) Isocyanate Capture: The highly reactive isocyanate intermediate is usually trapped in situ through hydrolysis, alcoholysis, or aminolysis.
Application Examples of Lossen Rearrangement
- Example 1: Dilan E. Polat and colleagues developed a versatile aza-Lossen rearrangement technique. This method transforms simple amine-derived N-hydroxyureas into complex hydrazine derivatives for synthesizing both cyclic and acyclic products. The reaction conditions accommodate internal or external nucleophiles, enabling chemoselective N-N bond formation to access semicarbazides and diverse heterocyclic derivatives. [2]
- Example 2: Neil A. Strotman et al. used nitrile activation (CH3CN, catalyst DBU, 60°C) of hydroxamic acid followed by Lossen rearrangement to generate the corresponding isocyanate. This strategy was successfully applied to the kilogram-scale synthesis of the HIV drug candidate BMS-955176 (55 kg, 95.5% isolated yield). [3]
Fig 2. Synthetic examples via Lossen rearrangement.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 320-322.
- Polat, Dilan E., et al. Organic Letters, 2019, 21(12), 4849-4852.
- Strotman, Neil A., et al. The Journal of Organic Chemistry, 2017, 82(8), 4044-4049.
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