Stille Coupling

General Procedure-1:

Halo-aromatic ring (1 eq.), tributyl (1-ethoxyvinyl) tin (1.2 eq.), Pd(PPh₃)₄ (0.05 eq.), and K₂CO₃ (1.2 eq.) are mixed in toluene (10 Vol). The mixture is degassed and heated to 100 ^oC for 2 hours under nitrogen atmosphere. The mixture is concentrated and the residue is mixed with 2N HCl. The resultant aqueous mixture is stirred for 2 hours and extracted with ethyl acetate. The organic layer is dried, concentrated, and the residue is separated by silica gel column chromatography to get the desired compound.

General Procedure-2:

A mixture of bromo-aromatic compound (1 eq.), Me₄Sn (10 equiv.), Pd(OAc)₂ (0.05 equiv.), and PPh₃ in DMF is heated to 100 ^oC for 30 min. The reaction is monitored by TLC. The resulting mixture is diluted with ethyl acetate, and washed with brine. The organic layer is dried and concentrated. The residue is purified by silica gel column chromatography.

Work-up tips:

• Bu₃SnX by-products can be removed by filtering through silica made up with ~2-5% triethylamine in the eluent or by washing the reaction mixture with a saturated aqueous solution of KF.

Note:

• Stille coupling is very similar to Suzuki coupling.

• As organotin compounds are air-stable, commercially available or easily synthesized, it is very popular. However, significant toxicity of organotin compounds and the difficulty to remove traces of tin-byproducts makes less preferable, as compared to Suzuki

• This reaction is highly stereospecific and regioselective, as similar to Suzuki.

• Reaction conditions are compatible with carboxylic acid, amide, ester, nitro, ethers, amine, hydroxyl, ketone, and formyl groups.

• For more details, refer to the tab “Reaction, Reagents & Mechanism”

Typical Procedure:

• Synthesis of a tetrathiophenylbenzene by Stille coupling (ChemSpider)

• Stille coupling of thiophene to 1,2,4,5-tetrabromo-3,6-bis(dodecyloxy)benzene (ChemSpider)

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WO2007121484, page no. 136

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:

• DMSO –Oxalyl Chloride (Swern Oxidation) (Reagent Guide, ACS Green Chemistry Institute)

• Potential Explosion Hazard associated with DMSO and its Mixtures (OPRD. 2020)