The Alchemy of Interruption

How a Twist on a Century-Old Reaction is Revolutionizing Molecular Design

Chemistry lab with molecular models

The Sulfur Symphony

In the orchestra of organic synthesis, sulfur compounds have long played supporting roles—odorous, temperamental, and prone to undesirable side reactions. Yet a groundbreaking approach has catapulted them to center stage: the interrupted Pummerer-sigmatropic rearrangement cascade. This elegant chemical ballet transforms simple sulfoxides into complex architectures like benzofurans (key structures in anticoagulants) and biaryls (found in OLED materials) with surgical precision 1 5 .

Key Advantages
  • No precious metals required
  • Redox-neutral process
  • High atom economy
  • Excellent regioselectivity
Molecular Structures
Benzofuran structure Biphenyl structure

Mechanism Decoded: A Four-Act Chemical Drama

The performance begins when an aryl or alkenyl sulfoxide (e.g., benzothiophene S-oxide) meets an activator like trifluoroacetic anhydride (TFAA). This step acylates the sulfoxide's oxygen, generating a hyper-reactive acyloxysulfonium ion 4 6 .

Here lies the genius interruption: Instead of proceeding to the classical Pummerer product, a π-nucleophile (allylsilane, phenol, or propargyl silane) attacks the sulfur atom. This forms a transient allyl sulfonium intermediate while sacrificing aromaticity—a daring move that unlocks new reactivity 1 5 .

The sulfonium species instantly undergoes a charge-accelerated sigmatropic shift. This reorganization, akin to a molecular tango, relocates bonds with near-perfect regioselectivity through a six-membered transition state 6 .

Aromacity rebounds as the system expels a leaving group. In benzothiophene functionalization, a final 1,2-migration installs substituents at the coveted C2 position 5 .

Traditional vs. Interrupted Pummerer Pathways
Stage Classical Pummerer Interrupted Cascade
Initial Step Sulfoxide O-acylation Sulfoxide O-acylation
Key Intermediate Thionium ion Allyl sulfonium ion
Nucleophile Role Attacks carbon (thionium) Attacks sulfur (sulfonium)
Primary Products α-Substituted sulfides Heterocycles, biaryls, dienes
Aromaticity Maintained Transiently lost, then restored

Spotlight Experiment: Crafting C2-Substituted Benzothiophenes

Methodology: A Four-Step Cascade

Yorimitsu's landmark 2018 study demonstrated how benzothiophene S-oxides—once considered synthetic dead ends—could yield C2-arylated products 5 :

  1. Activation: Benzothiophene S-oxide was treated with TFAA at -78°C, forming the acyloxysulfonium ion.
  2. Interruption: Addition of phenol derivatives triggered S-arylation, generating non-aromatic sulfonium salts.
  3. Rearrangement: Upon warming to 0°C, a [3,3]-sigmatropic shift occurred, creating a thiiranium intermediate.
  4. Migration: Spontaneous 1,2-migration restored aromaticity, delivering C2-functionalized benzothiophenes.
Results & Impact

The reaction achieved exclusive C2 selectivity—previously unattainable via direct C-H functionalization—with yields up to 95%. Electron-rich phenols outperformed electron-poor ones, reflecting the nucleophilicity dependence 5 .

Phenol Coupling Partner Yield (%) Selectivity (C2:C3)
4-Methoxyphenol 92 >99:1
4-Methylphenol 87 98:2
Phenol 78 95:5
4-Chlorophenol 62 90:10
4-Nitrophenol 18 80:20

This method bypassed the need for transition metals or pre-functionalized substrates, proving invaluable for synthesizing pharmaceutical intermediates like the anti-inflammatory Benzothiophene-2-carboxylates 5 .

The Scientist's Toolkit: Essential Reagents

Reagent Role Special Properties
Trifluoroacetic anhydride (TFAA) Sulfoxide activator Generates highly electrophilic sulfonium species
Allyl/propargyl silanes π-Nucleophiles Silicon stabilizes β-carbocation, enhancing rearrangement
Aryl sulfoxides Substrates Transient loss of aromaticity enables functionalization
2,6-Di-tert-butylpyridine Base Scavenges acids without nucleophilic interference
Benzothiophene S-oxides Heterocyclic substrates Readily oxidizable; form stable sulfonium salts
Safety Note: TFAA is highly corrosive! Reactions require anhydrous conditions and cryogenic handling 6 .

Beyond the Lab Bench: Real-World Applications

Drug Synthesis Leap

Indole alkaloids (e.g., anticancer agents vincristine) traditionally require 10+ synthetic steps. Procter's 2018 cascade enabled dual functionalization of indoles in one pot, installing thioether and allyl groups at adjacent positions—a feat unachievable via classical methods .

Materials Science Frontier

The reaction's regioselective biaryl coupling capability (e.g., terphenyl synthesis) offers a metal-free route to organic semiconductors used in flexible displays 1 6 .

Conclusion: Sulfur's Renaissance

Once dismissed as mere "smelly" auxiliaries, sulfoxides now drive a synthetic revolution. With its atom economy, step-efficiency, and innate selectivity, the interrupted Pummerer-sigmatropic cascade exemplifies how reimagining old reactions can solve modern challenges. As researchers expand its scope to photo-triggered variants and enantioselective versions, this chemistry promises cleaner routes to everything from antiviral drugs to quantum dot materials. In molecular design, sulfur has truly become the new carbon.

"This chemistry underscores the untapped potential of organosulfur compounds—they're not just odors; they're opportunities."

Prof. Hideki Yorimitsu (2017) 2

References