Stieglitz rearrangement

Although the original Stieglitz reaction is best known for the rearrangement of trityl hydroxylamines, there are several variations which include good leaving groups as N-substituents (such as halogens and sulfonates). Different reagents are commonly applied, depending on the exact nature of the substrate.^[4]

For the rearrangement of trityl hydroxylamines, Lewis acids such as phosphorus pentachloride (PCl₅), phosphorus pentoxide (P₂O₅) or boron trifluoride (BF₃) can be used.^[4] They function as electrophilic activators for the hydroxyl group by increasing the quality of the leaving group. For example, when using PCl₅ as a reagent, the trityl hydroxylamine is first transformed into the activated intermediate via a nucleophilic substitution.^[18] The generated intermediate can then undergo rearrangement by the migration of the phenyl group and dissociation of the phosphorus(V) species to form N-phenyl benzophenone imine.^[18]

Additionally to N-hydroxy trityl amines, rearrangements in N-alkoxy trityl amines are also possible. However, those reactions are known for their intrinsically low yields.^[19] For example, N-benzyloxy substituted trityl amine can undergo a Stieglitz rearrangement in the presence of phosphorus pentachloride (160 °C, 40% yield) or with BF₃ as a reagent (60 °C, 29% yield).^[20] In the latter case, BF₃ acts as a Lewis acid in the electrophilic activation of the benzylic oxygen to allow for a nucleophilic attack on the adjacent nitrogen atom.^[20]

Stieglitz rearrangements also readily proceed with active sulfonates as a leaving group.^[21] N-sulfonated amines can be obtained from the respective hydroxylamines and suitable sulfonation reagents. For example, Herderin et al. synthesized their secondary hydroxylamine (starting material in the rearrangement shown below) by subjecting the respective hydroxylamine to tosyl chloride and sodium hydroxide in acetonitrile.^[22]

The Stieglitz rearrangement is especially reactive in the case of bridged bicyclic N-sulfonated amines as starting materials, where mild conditions are sufficient for an efficient reaction to take place.^[23] For example, the rearrangement of the bicyclic N-tosylated amine proceeds readily in aqueous dioxane at room temperature.^[24] However, the respective imine is not formed in this case, presumably due to the strain that would thermodynamically disfavor such a structure, bearing a double bond at a bridgehead atom (Bredt's rule).^[25] Instead, the tosylate is nucleophilically added at the geminal position of the nitrogen via an attack on the iminium ion.^[22]

Stieglitz rearrangements can also proceed on organic azides with molecular nitrogen as a good leaving group.^[4] Those reactions proceed comparably to steps of the Schmidt reaction, by which carboxylic acids can be transformed into amines through the addition of hydrazoic acid under acidic aqueous conditions.^[26] The Stieglitz rearrangement of azides generally profits from a protonic^[16] or thermal^[4] activation, which can also be combined.^[10] In both cases, molecular nitrogen is set free as a gas in an irreversible step. It has been suggested that the rearrangement, after the dissociation of the N₂ molecule, proceeds over a reactive nitrene intermediate.^[10] These intermediates would be quite similar to those that have been proposed to be key intermediates in the rearrangement reactions named after Hofmann and Curtius,^[27] but have since been considered unlikely.^[28] When subjecting the azide to a Brønsted acid, the protonation of the azide activates the basal nitrogen and lowers the bond strength to the adjacent one, so that the dissociation and expulsion of molecular nitrogen is eased.^[16] After the rearrangement the proton can then dissociate from the iminium ion to yield the imine.

An alternative way for the production of protonated organic azides is the nuclophilic addition of hydrazoic acid to a carbocations, which can then also undergo Stieglitz rearrangements.^[16]

The Stieglitz rearrangement of N-halogenated amines can be observed for chlorine^[7] and bromine^[8] substituted amines, often in combination with an organic base, such as sodium methoxide.^[4] The need for a base is generally affiliated with the need for a deprotonation of the amine.^[4]

However, there also have been reported examples of base-free Stieglitz rearrangements of N-halogenated amines. An example for that can be found in the total synthesis of (±)-lycopodine by Paul Grieco et al.^[6][29] There, a ring formation takes place by a rearrangement on a secondary haloamine by subjecting it to silver tetrafluoroborate.^[6] AgBF₄ is known to act as a source of Ag⁺ ions that can facilitate the dissociation of halides from organic molecules, with the formation of the respective silver halide as a driving force.^[30] The desired product is then obtained by reduction with sodium cyanoborohydride, a mild reducing agent which is commonly employed in the reduction of imines to amines.^[31]

It was also observed, that the addition of lead tetraacetate can facilitate the Stieglitz rearrangement of amine derivatives.^[32] After the formation of the activated amine derivative intermediate by coordination to the lead center, the following rearrangement again proceeds via migration of the aromatic group under formation of a C–N bond, dissociation of lead and the deprotonation of the resulting iminium ion.^[33]

• Beckmann rearrangement
• Curtius rearrangement
• Dakin oxidation
• Schmidt reaction