Stephen-Castro reaction

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]. 

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. 

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]. 

The Stephens-Castro reaction generally requires heating in high-boiling solvents, but the reaction conditions can be substantially moderated by addition of a Pd-catalyst. Thus 2-iodopyridine is alkynylated (356) with phenylethynylcopper at room temperature with Pd-catalysis (82DOKU38). 

In the Stephens-Castro reaction 0-methylated 5-iodouracil has been reacted with THP-protected propargyl alcohol as a Cu-derivative to give the 5-alkynyl product (362). 

The reaction of aryl halides 29 with alkynylcoppers 30 is known as the Stephens-Castro reaction, which has proved to be particularly important in the synthesis of a wide... 

To avoid the isolation of the relatively unstable and often explosive Cu acetyhde, a modification of the original Stephens-Castro protocol involving generation of the alkynylcopper species in situ from the corresponding terminal acetylene and Cul in DMSO (dimethyl sulfoxide) or DMF (N,N-dimethylformamide) has been developed (9). The Stephens-Castro reaction can also be performed at sub-mol%... 

Recentiy, glyoxylyl chlorides 3, formed in situ by direct glyoxylation of electron-rich heterocycles such as indoles and pyrroles with oxalyl chloride, have been coupled in the Cu-catalyzed Stephen-Castro reaction to terminal arylacetylenes [11]. The resulting heterocycHc ynediones 4 are valuable electrophihc building blocks for the synthesis of various pharmaceutically relevant compounds (Scheme 9.3). 

Another noteworthy example of a modified Stephens-Castro reaction is the key step in the total synthesis of the natural product oximidine II (5) with distinct anticancer properties (Scheme 9.4) [12]. The Cu acetylide generated in situ from the terminal alkyne 6 using K2CO3 and Cul, underwent intramolecular cychzation followed by partial reduction of the acetylene unit to give the required macrocycUc triene skeleton 7. 

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... 

Some years later, Sonogashira and coworkers (1975) showed that both bromo-and iodoarenes and alkenes could be brought into reaction with terminal alkynes (in a direct extension of the Suzuki and Stephens-Castro reactions) in the presence of catalytic quantities of palladium(ll) (e.g., bis(triphenylphosphine)paUadium dichloride, ([C6H5]3P)2PdCl2, copper(l), e.g., cuprous iodide [Cul]), salts, and a primary (e.g., n-butylamine [CH3CH2CH2CH2NH2]) or secondary (e.g., diethyl-amine [(CH3CH2)2NH]) amine (Chapter 10). The details (Scheme 7.18) of this mild process (which are beyond the scope of this work) are thought to resemble the Heck (Chapter 6, Scheme 6.54) reaction in that a 7i-cloud-metal complex may play an intimate role. 

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