Castro–Stephens coupling explained

The Castro–Stephens coupling is a cross coupling reaction between a copper(I) acetylide and an aryl halide in pyridine, forming a disubstituted alkyne and a copper(I) halide.

The reaction was described in 1963 by chemists Castro and Stephens.^[1] The reaction is similar to the much older Rosenmund–von Braun synthesis (1914)^{[2] [3]} between aryl halides and copper(I) cyanide and was itself modified in 1975 as the Sonogashira coupling by adding a palladium catalyst and preparing the organocopper compound in situ, allowing copper to also be used catalytically.^{[4] [5]}

A typical reaction diphenylacetylene is obtained by the coupling of iodobenzene with CuC₂C₆H₅ in hot pyridine:^[1]

Unlike the Sonogashira coupling, the Castro–Stephens coupling can produce heterocyclic compounds when a nucleophilic group is ortho to the aryl halide, although this typically requires use of dimethylformamide (DMF) as solvent.^{[6] [7]}

Notes and References

1. The Substitution of Aryl Iodides with Cuprous Acetylides. A Synthesis of Tolanes and Heterocyclics. R. D.. Stephens. C. E.. Castro. J. Org. Chem.. 1963. 28. 12. 3313–3315. 10.1021/jo01047a008.
2. Rosenmund. Karl W.. Karl Wilhelm Rosenmund. Struck. Erich. Das am Ringkohlenstoff gebundene Halogen und sein Ersatz durch andere Substituenten. I. Mitteilung: Ersatz des Halogens durch die Carboxylgruppe. German. The halogen bound to the ring carbon and its replacement by other substituents. I. Notice: Replacement of the halogen by the carboxyl group. Ber. Dtsch. Chem. Ges. A/B. 1919. 52. 8. 1749–1756. 10.1002/cber.19190520840.
3. von Braun. Julius. Manz. Gottfried. Fluoranthen und seine Derivate. III. Mitteilung. German. Fluoranthene and its derivatives. III. Notification. Justus Liebigs Ann. Chem.. 1931. 488. 1. 111–126. 10.1002/jlac.19314880107.
4. Sonogashira. Kenkichi. Kenkichi Sonogashira. Tohda. Yasuo. Nobue. Hagihara. Tetrahedron Lett.. A convenient synthesis of acetylenes: Catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. 1975. 16. 50. 4467–4470. 10.1016/s0040-4039(00)91094-3.
5. Sonogashira. Kenkichi. Kenkichi Sonogashira. J. Organomet. Chem.. Development of Pd-Cu catalyzed cross-coupling of terminal acetylenes with sp²-carbon halides. 2002. 653. 1–2. 46–49. 10.1016/s0022-328x(02)01158-0.
6. Synthesis of natural isocoumarins, artemidin and 3-propylisocoumarin. Gunes. Batu. Robert. Stevenson. J. Org. Chem.. 1980. 45. 8. 1532–1534. 10.1021/jo01296a044.
7. Copper(I) Substitutions. Scope and Mechanism of Cuprous Acetylide Substitutions. Charles E.. Castro. R.. Havlin. V. K.. Honwad. A. M.. Malte. Steve W.. Moje. J. Am. Chem. Soc.. 1969. 91. 23. 6464–6470. 10.1021/ja01051a049.