Castro-Stephens coupling

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The Castro-Stephens coupling or Stephens-Castro coupling is an organic chemical name reaction . The reaction was discovered in 1963 by chemists Charles E. Castro and Robert D. Stephens . It has developed into an important synthesis tool in organic synthesis and combinatorial synthesis in medicinal chemistry.

The reaction is similar to the Rosenmund-von Braun reaction (1916), in which an aryl halide reacts with copper (I) cyanide to form aryl nitrile. The Sonogashira coupling (1975), in which the copper acetylide is produced in situ and the cross coupling is carried out with a palladium catalyst, is to be regarded as a further development of the Stephens-Castro coupling.

The Stephens-Castro coupling takes place by reacting the copper acetylide with an aryl halide in the presence of pyridine . The creation of a carbon-carbon bond creates an aromatic alkyne .

Overview of the Stephens-Castro coupling

Reaction mechanism

The course of the reaction starts from the terminal alkyne. This is first of copper (I) ion by forming a π-complex associated . Due to the considerable lack of electrons in the alkyne, the pKa value is reduced from approx. 30 to below 9. This activation can deprotonate the alkyne in the next step; pyridine is used for this. At the same time, an organic copper (I) compound is formed, to which the aryl iodide adds oxidatively. The less stable copper (III) compound thus formed breaks down in a rapid subsequent step by reductive elimination to give the arylalkyne and copper (I) iodide, which is a stoichiometric by-product.

disadvantage

The disadvantage of the Stephens-Castro coupling consists in the stoichiometric amounts of copper acetylides, which creates a risk of explosion. Another disadvantage is the use of boiling pyridine. For these reasons, the Sonogashira coupling, the Stille coupling or similar reactions are therefore preferably used nowadays.

literature

  • R. Brückner: Reaction mechanisms , 3rd edition, Spektrum Akad. Verlag, Munich, 2004 , p. 691. ISBN 3-8274-1579-9

See also

Individual evidence

  1. ^ RD Stephens and CE Castro: The Substitution of Aryl Iodides with Cuprous Acetylides. A Synthesis of Tolanes and Heterocyclics J. Org. Chem .; 28 ( 1963 ) 3313-3315, doi : 10.1021 / jo01047a008 .
  2. ↑ DC Owsley and CE Castro: Substitution of Aryl Halides with Copper (I) Acetylides: 2-Phenylfuro [3,2-b] Pyridine Template: link text check / apostrophe In: Organic Syntheses . 52, 1972, p. 128, doi : 10.15227 / orgsyn.052.0128 ; Coll. Vol. 6, 1988, p. 916 ( PDF ).