STEPHENS-CASTRO Acetylene

STEPHENS CASTRO Acetylene cycloptiane synthesis Polyacetylene cyclophane synthesis from an iodophenyl copper acetylide... 

STEGLICH HASSNER Dir t esterification 361 STEPHEN Aldehyde synthesis 362 STEPHENS CASTRO Acetylene cyclophana synthesis 363... 

Due to both the moderate yield and difficulties encountered in preparing large amounts of TEB by this procedure, a new route was developed based on the Hagihara (17) modification of the Stephens-Castro coupling (18). In this two-step procedure (Scheme 4), 1,3,5-tribromobenzene (VII) was coupled with a monoprotected acetylene using a Pd/Cu catalyst system. The protecting groups of the intermediate (IX) were then removed by a retro-Favorskii reaction (19). 

Unless otherwise stated, all manipulations are carried out under an atmosphere of argon using standard Schlenk techniques.13 The glassware used in the preparation of (2-iodophenyl)acetylene and the Stephens-Castro coupling of copper acetylide is dried in an oven at 140°C overnight. Potassium tm-butoxide (Aldrich)8 is sublimed at 150°C on a diffusion-pump vacuum... 

The substituted phenylacetylenes (6) were all prepared by a modified (2-6) Stephens-Castro coupling (7) of an aryl halide (3) with a monoprotected acetylene [2-methyl-3-butyn-2-ol (4, R = -C(CH3)20H) or trimethylsilyla-cetylene (4, R -81(0113)3)] in a refluxing dialkylamine solvent, followed by a deprotection step (Scheme I). 

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]. 

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%... 

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. 

Bis-acetylene synthesis from alkynyl halides and alkynyl copper reagents. Cf. Castro-Stephens reaction. 

Aryl-acetylene synthesis, Cf. Cadiot-Chodkiewicz coupling and Sonogashira coupling. The Castro-Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper. 

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. ... 

The procedure outlined above describes the selective, retentive, p-coupling of (Z)-2,3-dibromopropenoic acid ethyl ester with (trimethylsilyl)acetylene employing the palladium-modified version of the Castro-Stephens reaction.4 5 The dibromide starting material is readily available by bromination of ethyl propiolate (Procedure A), as described by Trippett and Hall.2 The coupling product has been shown to be a versatile precursor for the synthesis of variously substituted enynes and enediynes. For example, a second acetylene may be introduced into the a-position under modified coupling conditions. Alternatively, reduction of the ester with diisobutylaluminum hydride and protection of the resultant alcohol with tert-butyldiphenylsilyl chloride affords a vinyl bromide that can be metalated and trapped with various electrophiles. These procedures have been used on the gram and multigram scale.5... 

Inclusive reviews P. Cadiot, W. Chodkiewicz, Couplings of Acetylenes in Chemistry of Acetylenes, H. G. Viehe, Ed. (Marcel Dekker, New York, 1969) pp 597-647 K. Sonogashira, Comp. Org. Syn. 3, 551-561 (1991). Cf Castro-Stephens Coupling Ullmann Reaction. 

The cross-coupling between sp and sp carbon atoms was first discovered in 1963 by Stephens and Castro [1]. Their seminal report described the formation of an internal acetylene from a Cu(I) acetyHde and a phenyl or vinyl haHde (Scheme 9.1). In the original procedure, a variety of substituted tolanes were prepared in 75-99% yield by heating p- or o-substituted iodoarenes with cuprous phenylacetyUde in pyridine. 

Scheme 9.1 Formation of internal acetylenes from Cu(l) acetylides and aryl or vinyl halides according to Stephens and Castro [1].

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