Payne Rearrangement

What Is Payne Rearrangement?

The Payne rearrangement is a base-catalyzed isomerization of 2,3-epoxy alcohols in which the epoxide ring migrates from one position to another via an intramolecular S_N2 mechanism. The reaction converts a 2,3-epoxy alcohol into its isomeric 2,3-epoxy alcohol through a reversible epoxide migration, with the equilibrium position governed by the relative thermodynamic stability of the two epoxide isomers.

The Payne rearrangement holds a unique position in organic synthesis because it is a fully reversible process under thermodynamic control. While the equilibrium often favors the more substituted epoxide (due to the greater stability of the oxirane ring bearing alkyl substituents), the reaction can be driven in either direction by exploiting differences in the nucleophilic reactivity of the two epoxide isomers. For example, the less stable isomer, if consumed in a subsequent reaction (such as nucleophilic opening), can be continuously regenerated from the equilibrium mixture, enabling the overall transformation of the initially unfavored epoxide. This principle—Payne rearrangement followed by regioselective nucleophilic opening—has become a powerful strategic tool in complex molecule synthesis, particularly when combined with the Sharpless asymmetric epoxidation, which provides the enantiopure 2,3-epoxy alcohol starting materials.

• Reagents: Base (typically NaOH, KOH, or NaH in substoichiometric or catalytic amounts); solvent: aqueous or mixed aqueous-organic media (e.g., THF/H₂O), or anhydrous conditions (NaH in THF or DMF).
• Reactants: 2,3-Epoxy alcohols. The substrate must contain a free hydroxyl group at the α-position relative to the epoxide ring; primary, secondary, and tertiary alcohols are all competent.
• Products: Isomeric 2,3-epoxy alcohols, in which the epoxide oxygen has migrated to the carbon bearing the original hydroxyl group. The net transformation is a formal 1,2-migration of the epoxide ring.
• Reaction Type: Base-catalyzed intramolecular S_N2 epoxide migration.
• Related Reactions: Sharpless asymmetric epoxidation (provides the enantiopure epoxy alcohol starting materials); nucleophilic epoxide opening (often used to trap the desired Payne isomer); Jacobsen hydrolytic kinetic resolution (access to enantiopure epoxides); aza-Payne rearrangement (nitrogen analogue, rearrangement of N-activated aziridine alcohols).
• Experimental Tips: a) Base selection: The choice of base is critical. NaOH (0.1-1.0 equiv) in aqueous THF is the most common protocol. NaH is used in anhydrous conditions for substrates sensitive to aqueous base. b) Equilibrium control: The Payne rearrangement is reversible; the equilibrium ratio depends on the substitution pattern of the two epoxide isomers. The more substituted epoxide is generally thermodynamically favored. c) Trapping strategy: When the desired isomer is thermodynamically less favored, a nucleophile can be added to trap the minor isomer as it forms, driving the equilibrium through Le Chatelier's principle.

Fig 1. Payne rearrangement reaction and its mechanism. [1]

Mechanism of Payne Rearrangement

Step 1: Deprotonation of the Hydroxyl Group

The reaction is initiated by base-mediated deprotonation of the hydroxyl group of the 2,3-epoxy alcohol. This generates an alkoxide nucleophile, which is poised to attack the adjacent epoxide ring in an intramolecular fashion. The proximity of the alkoxide to the epoxide—a five-membered ring transition state geometry—is essential for the reaction to proceed efficiently.

Step 2: Intramolecular Epoxide Opening (SN2)

The alkoxide attacks the less hindered carbon of the epoxide ring in a 5-exo-tet fashion, opening the oxirane and forming a new epoxide ring at the carbon that originally bore the hydroxyl group. This step is a classic intramolecular S_N2 process proceeding through a five-membered cyclic transition state. The stereochemistry is governed by the S_N2 mechanism: the nucleophilic alkoxide attacks from the backside of the C-O bond, leading to inversion of configuration at the electrophilic carbon. Both the original epoxide carbon and the newly formed epoxide carbon undergo inversion, consistent with the overall stereochemical outcome of the rearrangement.

Step 3: Reversibility and Thermodynamic Control

A defining feature of the Payne rearrangement is its reversibility. The newly formed epoxide alcohol can undergo the same base-catalyzed isomerization to regenerate the starting material. The equilibrium position is determined by the relative thermodynamic stability of the two epoxide isomers. In general, the more substituted epoxide is favored because alkyl substitution stabilizes the oxirane ring through hyperconjugation and inductive effects. However, the equilibrium can be shifted by employing a nucleophile that selectively opens one of the epoxide isomers, thereby removing it from the equilibrium mixture and driving the reaction toward the desired isomer.

Application Examples of Payne Rearrangement

• Polyoxygenated Natural Products: The Payne rearrangement has been employed as a key step in the synthesis of numerous polyoxygenated natural products, including macrolide antibiotics, polyether ionophores, and complex carbohydrates. The ability of the reaction to interconvert epoxide regioisomers under mild conditions makes it ideally suited for the iterative construction of 1,2-diol and 1,3-diol motifs, which are ubiquitous in this class of natural products. The stereospecificity of the S_N2 rearrangement ensures that the relative and absolute configuration established at the epoxidation stage is faithfully preserved throughout the synthetic sequence.
• Combination with Sharpless Asymmetric Epoxidation: The strategic pairing of the Sharpless asymmetric epoxidation with the Payne rearrangement constitutes one of the most powerful approaches to chiral polyol synthesis. The Sharpless epoxidation provides enantiopure 2,3-epoxy alcohols with predictable absolute configuration. The Payne rearrangement then allows the epoxide to be repositioned to the desired location, and subsequent nucleophilic opening delivers the target diol or polyol with complete stereocontrol. This two-step sequence has been widely adopted in the synthesis of bioactive natural products and pharmaceutical intermediates.
• C-Glycoside Synthesis: The Payne rearrangement has been applied to the synthesis of C-glycosides and related carbohydrate mimetics. In these applications, the epoxide migration is used to install the correct stereochemistry at the anomeric position, and the rearranged epoxide is subsequently opened by a carbon nucleophile to form the C-glycosidic bond. This approach has proven particularly valuable for accessing β-C-glycosides, which are challenging to prepare by conventional glycosylation methods.

Fig 2. Synthetic examples via Payne rearrangement reaction. [2,3]

Related Products

CAS No.	Structure	Product
60456-23-7		(S)-Glycidol
6090-95-5		Conduritol b epoxide
391611-36-2		Spliceostatin A
102-76-1		Triacetin
86357-13-3		1,3-Diacetoxy-2-(acetoxymethoxy)propane
955016-25-8		(2S,4R)-4-Hydroxypiperidine-2-carboxylic acid,N-boc protected 95+%
184046-78-4		(2S,3S)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid methyl ester
1145663-09-7		(2S,4R)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate
135042-17-0		(2R,4S)-4-Hydroxypyrrolidine-1,2-Dicarboxylic acid 1-tert-butyl ester 2-methyl ester(N-boc-trans-4-hydroxy-d-proline methyl ester
2010-61-9		Benzenemethanol,4-methyl-a,a-bis(trifluoromethyl)-
225920-05-8		(S)-3',5'-Bis(trifluoromethyl)-1-phenethanol
95058-92-7		3-(2,2-Dimethyl[1,3]dioxolan-4-yl)-2,2-difluora-3-hydroxy-propionic acid ethyl ester
95798-23-5		Benzyl 4-hydroxy-1-piperidinecarboxylate
681508-70-3		4-Piperidinol,1-[4-(trifluoromethyl)phenyl]-
50-89-5		Thymidine
4753-04-2		2'-Chloro-2'-deoxyuridine
50-91-9		Floxuridine
59-14-3		Broxuridine

References

1. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 433-435.
2. Gholami, Hadi, et al. Angewandte Chemie International Edition 58.30 (2019): 10110-10113.
3. St-Gelais, Jacob, et al. Organic & Biomolecular Chemistry 18.20 (2020): 3903-3907.

Please kindly note that our products are for research use only.