Used extensively for pharmaceuticals (e.g., for hypertension) and agrochemicals. Buchwald-Hartwig Amination
Arylation—the installation of an aromatic ring onto a molecular scaffold—is arguably the most frequently performed operation in medicinal chemistry and agrochemical research. From non-steroidal anti-inflammatory drugs (NSAIDs) to conjugated polymers for OLEDs, the carbon-aryl bond is a ubiquitous structural motif. For decades, classical methods (Friedel-Crafts alkylation, nucleophilic aromatic substitution) dominated the landscape, albeit with severe limitations: harsh conditions, poor regioselectivity, and intolerable functional group compatibility. Used extensively for pharmaceuticals (e
Replacing Ir (expensive, scarce) with organic photocatalysts (e.g., 4CzIPN) or Ru. Pfizer scaled a C–O arylation to 50 kg using dual Ni/photoredox, avoiding traditional Ullmann conditions (140 °C, 24 h) – now 20 °C, 4 h. Used by Novartis, GSK, and Pfizer on >100 kg scale
Used by Novartis, GSK, and Pfizer on >100 kg scale. Still limited by surfactant removal and recycling. Yield: 87% → 94%
Artificial metalloenzymes (e.g., Pd embedded in a protein scaffold) can perform Suzuki couplings in water at 37 °C with ppm metal. Not yet robust, but a single proof-of-concept at Genentech suggests future biocatalytic arylation.
Allows Suzuki, Heck, and Buchwald-Hartwig in water at room temperature. Eliminates organic solvents, simplifies workup (product extracted with MTBE, catalyst stays in micelles).
Replaced BINAP with RuPhos (more electron-rich, oxidatively stable). Replaced NaOt-Bu with K₂CO₃ (milder, insoluble – requires phase-transfer catalyst, Aliquat 336). Ran at 90 °C instead of 110 °C. Yield: 87% → 94%, with full conversion.