What Is Castro-Stephens Coupling?
The Castro-Stephens coupling reaction involves the coupling of aromatic halides with copper(I) acetylide in boiling pyridine. This reaction results in the formation of a disubstituted alkyne and a copper(I) halide. It was first described in 1963 by chemists Charles E. Castro and Robert D. Stephens.
The Castro-Stephens coupling was later modified as the Sonogashira coupling in 1975, which added a palladium catalyst and allowed for the preparation of the organocopper compound in situ, enabling the use of copper as a catalyst.
The Castro-Stephens coupling has the ability to produce heterocyclic compounds when a nucleophilic group is located ortho to the aryl halide, although this typically requires the use of dimethylformamide (DMF) as a solvent.
The Castro-Stephens coupling reaction has an alternative mechanism similar to the Cadiot-Chodkiewicz coupling reaction.
Fig 1. Castro-Stephens coupling reaction and its mechanism. [1]
Improvements and Applications of Castro-Stephens Coupling
- Example 1: Miura improved the Castro-Stephens coupling reaction, using only PPh3 and catalytic amount of CuI, with K2CO3 as base [reaction conditions: CuI (Cat.), Ph3P, K2CO3, DMF, 120 °C]. This modification was used for intramolecular cross-coupling of olefinic iodide and alkyne, and the yield of the reaction depended on the substituents on the ring. [2]
- Example 2: Another modification of the Castro-Stephens coupling reaction is to use terminal alkynes and aromatic halides for direct coupling in the presence of cuprous iodide and triethylamine. Due to the mild reaction conditions, White successfully applied this modification to the total synthesis of anticancer natural products Epothilone B, Epothilone D and cis- and trans-9,10-dehydroepothilone D. This modification was also used by Schreiber to construct a library of functional group-dense polycyclic compounds, which was used in chemical genetics research. [3]
Fig 2. Synthetic examples via Castro-Stephens coupling reaction.
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References
- Li, Jie Jack. Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications Fifth Edition, 2014, 10-111.
- Okuro, Kazumi, et al. The Journal of Organic Chemistry, 1993, 58(17), 4716-4721.
- White, James D., et al. Journal of the American Chemical Society, 2001, 123(23), 5407-5413.
