Pummerer Rearrangement

What Is Pummerer Rearrangement?

The Pummerer rearrangement is the conversion of a sulfoxide bearing at least one alpha-hydrogen atom into an alpha-acyloxy sulfide (or alpha-substituted sulfide) upon treatment with an acid anhydride or an acid chloride. The reaction proceeds through a thionium ion intermediate, which can be intercepted by a variety of nucleophiles. The reaction was first reported in 1909 by Rudolf Pummerer, a German chemist, after whom it is named.

The Pummerer rearrangement has evolved from a niche sulfoxide transformation into a versatile synthetic methodology. The classical protocol employs acetic anhydride or trifluoroacetic anhydride as the activating agent, generating the thionium ion which is captured by the acetate nucleophile. Modern variants, including the additive Pummerer reaction (using silyl ketene acetals or other carbon nucleophiles), the vinylogous Pummerer reaction, and the interrupted Pummerer reaction, have greatly expanded the scope of products accessible through this chemistry. Catalytic enantioselective variants using chiral Lewis acids or organocatalysts have also been developed. The reaction is now widely used for C-C, C-N, and C-O bond formation at the alpha-position of sulfides.

• Reagents: Classical: acetic anhydride (Ac₂O), trifluoroacetic anhydride (TFAA). Modern variants: silyl ketene acetals, allylsilanes, enol ethers; chiral Lewis acids for asymmetric variants; oxidants for sulfoxide preparation (m-CPBA, NaIO₄).
• Reactants: Sulfoxides bearing at least one alpha-hydrogen atom (R-S(=O)-CHR¹R²). Aryl, alkyl, and vinyl sulfoxides are all competent substrates.
• Products: Alpha-acyloxy sulfides (classical); alpha-substituted sulfides (e.g., alpha-allyl, alpha-aryl, alpha-vinyl sulfides) when using carbon nucleophiles. The sulfur atom is reduced from S(IV) to S(II) while the alpha-carbon is oxidized.
• Reaction Type: Sulfoxide activation-rearrangement.
• Related Reactions: Swern oxidation (DMSO activation with (COCl)₂); Polonovski reaction (N-oxide activation with Ac₂O); additive Pummerer reaction; vinylogous Pummerer; interrupted Pummerer reaction.
• Experimental Tips:
  a) Sulfoxide preparation: The starting sulfoxide is typically prepared by oxidation of the corresponding sulfide with m-CPBA or NaIO₄.
  b) Choice of anhydride: TFAA generally provides faster reaction rates than Ac₂O and can be used at lower temperatures.

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

Mechanism of Pummerer Rearrangement

Step 1: Sulfoxide Activation

The reaction is initiated by acylation of the sulfoxide oxygen with an acid anhydride (acetic anhydride or TFAA). This generates an acyloxysulfonium salt, which is highly electrophilic at the alpha-carbon. The acylation renders the sulfoxide oxygen a good leaving group and activates the alpha-C-H bonds toward deprotonation.

Step 2: Thionium Ion Formation

The acyloxysulfonium intermediate undergoes elimination of the carboxylate leaving group with concomitant deprotonation at the alpha-position, generating a thionium ion (also referred to as a sulfonium ion or thiocarbonium ion). This cationic intermediate is resonance-stabilized and highly electrophilic at the alpha-carbon. The driving force for this step is the aromatization or charge delocalization that accompanies thionium ion formation.

Step 3: Nucleophilic Capture

The thionium ion is intercepted by a nucleophile. In the classical Pummerer reaction, the nucleophile is the acetate ion (generated from the anhydride), which adds to the electrophilic alpha-carbon to produce the alpha-acetoxy sulfide. In modern variants, a wide range of carbon, nitrogen, and oxygen nucleophiles can be employed, allowing the introduction of diverse functionality at the alpha-position. The regioselectivity is governed by the stability of the thionium ion and the relative reactivity of the competing nucleophiles present in the reaction mixture.

Application Examples of Pummerer Rearrangement

• C-C Bond Formation via Additive Pummerer: The additive Pummerer reaction, in which an external nucleophile (e.g., allylsilane, silyl enol ether, or electron-rich arene) is added to trap the thionium ion, has become a powerful method for C-C bond formation. This variant provides access to alpha-allyl, alpha-vinyl, and alpha-aryl sulfides with high efficiency and predictable regiochemistry. M Šiaučiulis et al. achieved bi-ortho functionalization of heterocycles through interrupted Pummer coupling/[3,3]-σ rearrangement cascade reactions. [2]
• Heterocycle Synthesis: The Pummerer rearrangement has been extensively employed in the synthesis of nitrogen- and oxygen-containing heterocycles. The thionium ion intermediate can be trapped intramolecularly by tethered nucleophiles (amides, alcohols, or electron-rich aromatics), leading to the construction of indoles, isoquinolines, benzofurans, and other heterocyclic systems in a single operation.
• Enantioselective Pummerer Reactions: Recent advances in asymmetric catalysis have enabled enantioselective Pummerer rearrangements. Chiral Lewis acids, Bronsted acids, and organocatalysts have been employed to control the absolute configuration at the newly formed alpha-stereocenter. These methods provide access to enantioenriched sulfides that serve as valuable chiral building blocks.
• Total Synthesis Applications: The Pummerer rearrangement and its variants have been utilized as key steps in the total synthesis of several natural products and bioactive molecules, where the ability to functionalize the alpha-position of sulfides allows rapid assembly of complex molecular architectures. Xin Li et al. reported a strategy for the total synthesis of aromatic abside diterpenoids using the Pummer rearrangement reaction. [3]

Fig 2. Synthetic examples via Pummerer rearrangement reaction.

Related Products

CAS No.	Structure	Product
70-29-1		Diethyl sulfoxide
17396-36-0		Thian-4-one s-oxide
120-62-7		Sulfoxide
111031-14-2		Clethodim sulfoxide
1115-15-7		Divinyl sulfoxide
1193-82-4		Methyl phenyl sulfoxide
124751-36-6		Cevimeline sulfoxide
14094-11-2		tert-Butyl methyl sulfoxide
1519-39-7		(R)-(+)-Methyl p-tolyl sulfoxide
152406-99-0		s-(4-Bromophenyl)cysteine sulfoxide
15733-02-5		Methyl(4-phenylbutyl)sulfoxide
15785-31-6		Dl-ethionine sulfoxide
1646-87-3		Aldicarb-sulfoxide
1774-35-2		4,4-Dimethyldiphenylsulfoxide
19093-37-9		Allyl phenyl sulfoxide

References

1. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 462-464.
2. Šiaučiulis, Mindaugas, et al. Chemical Science 9.3 (2018): 754-759.
3. Li, Xin, et al. Organic letters 20.18 (2018): 5546-5549.

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