Pyridines Castro-Stephens reaction

In a laboratory-scale synthesis of rofecoxib (2), a ruthenium-catalyzed lactonization of diarylacetylene 19 gave rise to 2 regioselectively (Scheme 4)." Diarylacetylene 19, on the other hand, was prepared by utilizing a Castro-Stephens reaction of p-iodophenyl methyl sulfone and copper(I) phenylacetylene in pyridine under reflux. In another case, Fallis and coworkers synthesized butenolide in 2 using a magnesium-mediated carbometallation reaction. Therefore, treatment of... 

The Castro-Stephens reaction entails coupling of alkynylcopper(I) reagents with aryl or heteroaromatic halides in refluxing pyridine to furnish arylacetylenes. The cuprous alkynylides are prepared by adding the 1-alkynes to an aqueous ammonia solution of cuprous iodide. Since dry copper alkynylides have the tendency to explode, they must be handled with great care and should only be used in a slightly damp state. ... 

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... 

The reaction of aryl halides 1 with alkynylcopper(I) 2 under reflux in pyridine to prepare internal arylacetylenes is known as the Stephens-Castro reaction [Eq. (1)] [2]. The reaction has proved to be particularly important in the synthesis of a wide range of tolan and heteroaromatic alkynes [3]. Vinyl and allenic halides can also be used and several reviews... 

As described above (Section 5.2), the Stephens-Castro reaction of alkynylcopper with aryl and vinyl halides in boiling pyridine is a useful route to aryl and vinyl acetylenes. Direct cross-coupling of organic halides, such as sp halides, with terminal alkynes is a more convenient procedure. Such a reaction is not so easy, but it can be done using a Pd-complex catalyst [41]. Especially facile Pd-catalyzed cross-coupling of aryl and alkenyl halides with terminal alkynes proceeds smoothly under mild conditions in the presence of a cocatalyst of cuprous iodide in amine solvents [Eq. (28)] [42]. This methodology is now used widely for the constiuction of conjugated arylalkyne or enyne systems [43], as described below. It is attractive from a synthetic point of view because mild reaction conditions and simplicity of the procedure are associated with recent developments in modem acetylene chemistry [44]. 

The majority of reported reactions of aryl and heteroaryl substrates with organocopper reagents are examples of Stephens-Castro coupling or the more recent catalytic version of that reaction. The reaction has found recent application in syntheses of C-(6)-substituted pterins and pteridines, substituted pyridines, and the antitumor antibiotic fredericamycin A," to name a few. Aryl iodide can be che-mospecifically displaced in the presence of bromide," and 2,5-dibromopyridine is regioselectively substituted at the 2-position. Substitution of halobenzenes by propargyl alcohol, followed by oxidative cleavage, provides a convenient route to terminal arylalkynes. " Fused heterocycles are formed in reactions of aryl halides bearing nucleophilic ortho substituents. - "... 

Alkynyl derivatives have been prepared by the Stephens-Castro reaction (Scheme 82). 3,5-Diiodo-4( 1H)-pyridinone without 0-protection is monocoupled with phenylethynylcopper. The 5-alkynyl product subsequently suffers Michael attack from the vicinal oxygen function to form a fused product, a furo[3,2-c]pyridine (355) [66JOC4071 87ACSA(B)219 89JCS(P1)1165]. 

In 1975, three different protocols were available in the literature, each describing the synthesis of internal alkynes. Cassar described palladium- or nickel-mediated reactions between aryl or vinyl halides and alkynes complexes with phosphine as ligands in the presence of NaOMe [1]. As a second protocol, Heck pubhshed a variation of the Mizoroki-Heck couplings, in which the olefins were replaced by alkynes and coupled with (hetero)aryl, as weU as alkenyl bromides or iodides at 100 °C in the presence of a basic amine [2]. More than a decade earUer, Stephens and Castro had described the details of a palladium-free coupling of aryl iodides with cuprous acetylides in refluxing pyridine [3]. 

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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