& Mechanism
Green Chem
& Mechanism
Reaction & Reagents info
- Negishi coupling: C-C bond formation involving organohalides and organozinc reagents
- Reactant-1 (Nucleophile): Organozinc reagent
- Reactant-2 (Electrophile): Organohalide
- Solvents: THF,
- Catalyst: Catalytic Palladium or Nickel
- Ligand: PPh3, dppe, dppp, dppb, dppf, etc.
Useful Links on Reagent & Reaction:
- Negishi Coupling (SynArchive) – Excellent compilation of reaction schemes with references
Mechanism
Negishi Coupling – General Mechanism (Pd catalyzed)
- The mechanism follows Oxidative addition – Reductive elimination cycle.
Negishi Coupling – General Mechanism (Ni catalyzed)
Ref: J. Am. Chem. Soc. 2013, 135, 8141; J. Org. Chem. 2008, 73, 3680
Negishi Coupling – Mechanism with specific example
Additional details
General Procedure:
Note:
- The major advantages of Negishi coupling is high reactivity, high regio- and stereoselectivity, few side reactions and little toxicity.
- Organozincs (for Negishi coupling) are more reactive than organoboranes (for Suzuki coupling) and organostannanes (for Stille coupling).
- Organozinc reagents are generally unstable towards moisture and air. Hence, most of organozinc reagents are not commercially available and are to be generated.
For more details, refer to the tab “Reaction, Reagents & Mechanism”
Typical Procedure:
WO2007121484, page no. 174 (to be changed)
Green Chem
Swern oxidation could be carried out on large-scale. However, the reaction involves the liberation of 1 eq. each of the gases such as Me2S (dimethylsulphide), CO (carbon monoxide), CO2. Appropriate safety controls are to be ensured while performing manufacturing. During work-up, HCl gets converted to amine salt (such as NEt3.HCl).
- Swern Oxidation is one of the inexpensive methods to manufacture aldehydes or ketones from Alcohols
- The liberation of gases viz., malodrous dimethylsulphide (Me2S), poisonous carbon monoxide (CO) and CO2 are to be handled appropriately
- It is important to maintain the reaction mixture at -78 oC. If the temperature is not maintained, there is a possibility of formation of mixed thioacetals (see mechanism in General Info section)
Scale-Up Typical Procedure:
- An Improved and Efficient Process for the Production of Donepezil Hydrochloride (OPRD, 2008) – 4 Kg batch; 3.5 Kg of DMSO & 3.7 Kg of (COCl)2 have been used
- Convergent Catalytic Asymmetric Synthesis of Camptothecin Analog GI147211C (Tetrahedron, 1997) – 100 g batch
Green Chemistry Aspects: