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Meyer–Schuster rearrangement

The Meyer–Schuster rearrangement is the chemical reaction described as an acid-catalyzed rearrangement of secondary and tertiary propargyl alcohols to α,β-unsaturated ketones if the alkyne group is internal and α,β-unsaturated aldehydes if the alkyne group is terminal.^[1] Reviews have been published by Swaminathan and Narayan,^[2] Vartanyan and Banbanyan,^[3] and Engel and Dudley,^[4] the last of which describes ways to promote the Meyer–Schuster rearrangement over other reactions available to propargyl alcohols.

Mechanism

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The reaction mechanism^[5] begins with the protonation of the alcohol which leaves in an E1 reaction to form the allene from the alkyne. Attack of a water molecule on the carbocation and deprotonation is followed by tautomerization to give the α,β-unsaturated carbonyl compound.

Edens et al. have investigated the reaction mechanism.^[6] They found it was characterized by three major steps: (1) the rapid protonation of oxygen, (2) the slow, rate-determining step comprising the 1,3-shift of the protonated hydroxy group, and (3) the keto-enol tautomerism followed by rapid deprotonation.

In a study of the rate-limiting step of the Meyer–Schuster reaction, Andres et al. showed that the driving force of the reaction is the irreversible formation of unsaturated carbonyl compounds through carbonium ions.^[7] They also found the reaction to be assisted by the solvent. This was further investigated by Tapia et al. who showed solvent caging stabilizes the transition state.^[8]

The reaction of tertiary alcohols containing an α-acetylenic group does not produce the expected aldehydes, but rather α,β-unsaturated methyl ketones via an enyne intermediate.^[9][10] This alternate reaction is called the Rupe reaction, and competes with the Meyer–Schuster rearrangement in the case of tertiary alcohols.

While the traditional Meyer–Schuster rearrangement uses harsh conditions with a strong acid as the catalyst, this introduces competition with the Rupe reaction if the alcohol is tertiary.^[2] Milder conditions have been used successfully with transition metal-based and Lewis acid catalysts (for example, Ru-^[11] and Ag-based^[12] catalysts). Cadierno et al. report the use of microwave-radiation with InCl${\displaystyle _{3}}$ as a catalyst to give excellent yields with short reaction times and remarkable stereoselectivity.^[13] An example from their paper is given below:

The Meyer–Schuster rearrangement has been used in a variety of applications, from the conversion of ω-alkynyl-ω-carbinol lactams into enamides using catalytic PTSA^[14] to the synthesis of α,β-unsaturated thioesters from γ-sulfur substituted propargyl alcohols^[15] to the rearrangement of 3-alkynyl-3-hydroxyl-1H-isoindoles in mildly acidic conditions to give the α,β-unsaturated carbonyl compounds.^[16] One of the most interesting applications, however, is the synthesis of a part of paclitaxel in a diastereomerically-selective way that leads only to the E-alkene.^[17]

The step shown above had a 70% yield (91% when the byproduct was converted to the Meyer-Schuster product in another step). The authors used the Meyer–Schuster rearrangement because they wanted to convert a hindered ketone to an alkene without destroying the rest of their molecule.