Copper acetylide Castro-Stephens reaction

The Castro-Stephens reaction is the cross coupling of a copper acetylide (1) and an aryl or vinyl halide (2) to give a disubstituted alkyne (3). The reaction, which shares some common elements with the Sonogashira, Cadiot-Chodkiewicz, Rosenmund-von Braun, Hay, and Glaser coupling reactions, was discovered by Stephens and Castro in the early 1960s and has found some applications in synthesis. " ... 

This synthesis included a Castro-Stephens-type coupling of two highly functionalized fragments, where 69, and allylic bromide 70, together with EtsN and Cul, were heated to 50 °C in an Et20/DMF solvent system. With this treatment, a 60% yield of the coupled product 71 was obtained. There are several other examples of allylic substitution with copper acetylides, and these reactions clearly occur under milder conditions than typical Castro-Stephens couplings. This reaction may be more of an Sn2 displacement, however, the net transformation and reaction conditions bear some similarity to the Castro-Stephens reaction. 

The Cadiot-Chodkiewicz coupling typically proceeds under conditions which are considerably milder than Castro-Stephens reactions. Triethylsilylacetylene 74 rapidly undergoes Cadiot-Chodkiewicz coupling with alkynyl bromide 75 to generate the unsymmetrical bisalkyne 76 in nearly quantitative yield when those two reactants are treated with catalytic cuprous chloride and catalytic ammonium hydroxide in -butylamine solution. This coupling process affords one of the best entries into compounds such as 76 and is permissive of TES and larger silylated copper acetylide species because of the lower reaction temperature. ... 

Terminal alkynes can be alkenylated by alkenyl triflates (bromides, iodides) and aryl-ated by aryl triflates (bromides, iodides). These reactions are called Cacchi coupling reactions if the reaction is catalyzed by Cu(I) and Pd(0) and if triflate reagents are employed, Sonogashira-Hagihara coupling reactions if the reaction is catalyzed by Cu(I) and Pd(0) and halides are employed as substrates, and Stephens-Castro coupling reactions for the more specialized case of the noncatalyzed coupling of copper acetylides with aryl halides. 

The Castro-Stephens coupling also involves the reaction of copper(I) acetylide with aryl halides to form diarylacetylenes. 

In this variation of the Pd-catalyzed cross-coupling reaction, which is closely related to the Stephen-Castro reaction, copper acetylides are reacted with (hetero)aryl halides or triflates to produce (hetero)aryl alkynes [111]. The Sonogashira reaction is comparable to the Suzuki or Stille reactions in its scope and functional group tolerability. 

Under certain conditions, alkynes can be coupled to aryl halides.280 When aryl halides react with copper acetylides to give 1-aryl alkynes such as 431, the reaction is known as Stephens-Castro coupling.28l Both aliphatic and aromatic substituents can be attached to the alkyne unit, and a variety of aryl iodides has been used. A palladium-catalyzed variation is also known in which an aryl halide reacts with a terminal alkyne to give derivatives such as 434. In this variation, called the Sonogashira coupling,2 2 jhe reaction is catalyzed by... 

For cross-coupling reactions between iodoarenes and stoichiometric amounts of copper acetylides in the absence of palladium compounds, see (a) Castro, C.E. and Stephens, R.D. (1963) J. Org. Chem., 28, 2163 ... 

Compounds like tribenzocyclotriyne 47 are of interest because they have the ability to form conducting complexes with low-valent nickel by virtue of their planar, anti-aromatic character and cavity size. Youngs et al. published a synthesis of 47 where cyclotrimerization of precursor 48 is accomplished by S3mthesizing and then purifying the copper acetylide of the latter iodo alkyne and then refluxing said material in pyridine for 24 hours. In this way, the desired cyclotrimer 47 is obtained in an impressive 80% yield. The palladium-based Sonogashira reaction was attempted for this same substrate (48) and was much less effective (5% yield of 47). There are several examples where the Castro-Stephens approach was superior to other methods for creating cyclic arene/yne macrocycles. ... 

In 1963, Castro, Stephens, and co-workers reported a novel indole formation from 2-iodoaniline 201 and copper acetylides 202 in DMF (Scheme 19.52) [97]. When the reaction was conducted in pyridine, the product composition varied from exclusively uncyclized 2-alkynylindoles 199a to mixtures of 200a and 199a, depending on the nature of the acetylide. They confirmed that the cyclization of 199a to 200a... 

Castro and Stephens developed a method for the preparation of unsymmetrical disubstituted acetylenes, which involves the reaction of copper(I) acetylides with aromatic iodo compounds. Bond and Hooper extended this route to the preparation of 2-aryIisatogens (22). 2-Nitro-phenylpropiolic acid (19a) is readily decarboxylated to the acetylene (19b), which on treatment with copper (I) chloride gives 19c. The reaction of 19c with substituted aromatic iodo compounds (20) gives the corresponding acetylenes (21), which subsequently cyclize to the isatogens (22). The alternative route (23 + 24 - 21) has been little used. ... 

Processes similar to the Suzuki coupling reaction have been observed with alkynes. Thus, the Stephens-Castro reaction between unsaturated iodides (aryl, vinyl) and copper(l) acetylides in pyridine solvent results in the formation of new... 

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