& Mechanism
Green Chem
& Mechanism
Reaction & Reagents info
- Sonogashira coupling: C-C bond formation involving aryl or vinyl halides with terminal alkynes to generate conjugated enynes and arylalkynes.
- Reactant-1 (Nucleophile): Terminal Alkyne
- Reactant-2 (Electrophile): Organohalide
- Solvents: THF, CH3CN, EtOAc
- Catalyst: Catalytic Palladium [Pd(PPh3)4 (tetrakis), (Ph3P)2PdCl2 (dikis)] & Cu(I) salt [CuI or CuBr]
- Bases: Et3N
Useful Links on Reagent & Reaction:
- Sonogashira Coupling (SynArchive) – Excellent compilation of reaction schemes with references
Mechanism
Sonogashira Coupling – General Mechanism
- The mechanism follows Oxidative addition – Reductive elimination cycle.
- Palladium and copper co-catalyzed Sonogashira coupling is reported to proceed via two independent catalytic cycles
Stille Coupling – Mechanism with specific example
Additional details
General Procedure-1 :
A mixture of Bromo-aromatic ring (1 eq ), alkyne derivative (1 eq), bis(triphenyl phsophine)palladium [II]cholride (0.025eq ) and CuI (0.1eq ) were taken in freshly distilled DIPEA (10 Vol). The mixture degassed, and stirred at room tempperature overnight under nitrogen atmosphere. The reaction was quenched with aq. NH4Cl (10 Vol, 10% solution) and extracted with EtOAc. The solvent was distilled off and the resultant residue was purified by silica gel column to get the desired compound.
Note:
- This reaction is highly stereospecific and regioselective, as similar to Suzuki.
- The general trend of substrate reactivity towards oxidative addition:
vinyl iodide ≥ vinyl triflate > vinyl bromide > vinyl chloride > aryl iodide > aryl triflate ≥ aryl bromide >> aryl chloride
- The terminal alkyne substrate exhibits a relatively broad range of functional group compatibility
For more details on reaction and reagents, refer to the tab “Reaction, Reagents & Mechanism”
For more details on large-scale reactions, refer to the tab “Scale-up & Green Chem”
Typical Procedure:
WO2007121484, page no. 174
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: