What Is Meyer-Schuster Rearrangement?
The Meyer-Schuster rearrangement is an atom-economical, acid-catalyzed transformation that converts propargylic alcohols into α,β-unsaturated carbonyl compounds via a formal 1,3-shift, proceeding through an allenol intermediate. It enables the conversion of secondary and tertiary propargylic alcohols into α,β-unsaturated carbonyl compounds—specifically, α,β-unsaturated ketones if the alkyne is internal, and α,β-unsaturated aldehydes if the alkyne is terminal. The reaction was first reported in 1922 by Kurt H. Meyer and Kurt Schuster, after whom it is named.
While these protocols were synthetically useful, they were plagued by several limitations: narrow functional group tolerance, competing pathways (particularly the Rupe rearrangement), and the need for harsh conditions that could degrade sensitive substrates. The past two decades have witnessed a revolution in this field, with the development of mild transition-metal-catalyzed variants (notably using gold(I), ruthenium(II), scandium(III), iron(III), and other Lewis acids), organocatalytic systems employing Brønsted acids under milder conditions, and green chemistry approaches such as microwave-assisted and aqueous-media protocols.
- Reagents: Brønsted acids (e.g., H2SO4, p-TsOH, H3PO2) or Lewis acids / transition-metal catalysts (e.g., Au(I), Ru(II), Sc(III), Fe(III), Ga(III), Ca(II), Ag(I), Cu(I)).
- Reactants: Secondary or tertiary propargylic alcohols (R1R2C(OH)–C≡C–R3, where R3 = H or alkyl/aryl).
- Products: α,β‑Unsaturated carbonyl compounds: If R3 = H → α,β‑unsaturated aldehyde; If R3 = alkyl/aryl → α,β‑unsaturated ketone.
- Reaction Type: 1,3‑hydroxy shift; atom‑economic rearrangement.
- Related Reactions:
– Rupe rearrangement (competitive pathway for tertiary propargylic alcohols with β‑hydrogens, giving different enone isomers).
– Aza‑Meyer-Schuster rearrangement (using propargylic amines to give α,β‑unsaturated imines).
Fig 1. Meyer-Schuster rearrangement reaction and its mechanism. [1]
Mechanism of Meyer-Schuster Rearrangement
Classical Acid-Catalyzed Pathway
The classical mechanism proceeds via an acid-catalyzed formal 1,3-shift of the hydroxyl group. As depicted in general texts and mechanistic studies, the reaction is initiated by protonation of the propargylic alcohol to form a carbocation at the propargylic position. Water loss generates a resonance-stabilized propargyl-allenyl cation pair, which is captured by water to produce an allenol intermediate. Tautomerization of this allenol furnishes the α,β-unsaturated carbonyl product.
Transition-Metal-Catalyzed Pathway
Transition-metal catalysis, particularly with gold(I) complexes, has provided an alternative mechanistic manifold that avoids the formation of free carbocations and thus enables mild conditions. In gold-catalyzed Meyer-Schuster rearrangements, the gold catalyst coordinates to the alkyne π-bond, activating it toward nucleophilic attack. The oxygen of the propargylic alcohol acts as an internal nucleophile, forming an oxonium or related intermediate. This pathway typically proceeds under ambient conditions and exhibits excellent functional group tolerance.
Application Examples of Meyer-Schuster Rearrangement
The Meyer-Schuster rearrangement has been featured as a key step in numerous total syntheses of complex natural products, a testament to its reliability, mildness, and functional group compatibility. [2]
- Prostaglandins and Drug Analogs: Gold(I)-mediated Meyer-Schuster rearrangement was developed for the installation of the “lower” side chain of prostaglandins and their drug analogs (Bimatoprost and Latanoprost). This approach, featuring low catalyst loading and mild reaction conditions, provides an efficient alternative to the standard Horner-Wadsworth-Emmons reaction in prostaglandin chemistry.
- Fuligocandins A and B: The practical total synthesis of fuligocandins A and B, cycloanthranilylproline derivatives isolated from the myxomycete Fuligo candida, was achieved efficiently by a Meyer-Schuster rearrangement that delivered the Z-isomer with high selectivity.
Fig 2. Synthetic examples via Meyer-Schuster rearrangement reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 345-347.
- Justaud, Frédéric, et al. European Journal of Organic Chemistry 2021.4 (2021): 514-542.
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