Castro coupling

Unactivated aryl halides react with copper acetylides to give good yields of arylacetylenes Stephens-Castro coupling)P ... 

In 1988, Linstrumelle and Huynh used an all-palladium route to construct PAM 4 [21]. Reaction of 1,2-dibromobenzene with 2-methyl-3-butyn-2-ol in triethylamine at 60 °C afforded the monosubstituted product in 63 % yield along with 3% of the disubstituted material (Scheme 6). Alcohol 15 was then treated with aqueous sodium hydroxide and tetrakis(triphenylphosphine)palladium-copper(I) iodide catalysts under phase-transfer conditions, generating the terminal phenylacetylene in situ, which cyclotrimerized in 36% yield. Although there was no mention of the formation of higher cyclooligomers, it is likely that this reaction did produce these larger species, as is typically seen in Stephens-Castro coupling reactions [22]. 

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... 

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. 

More often such bromo- and iodoalkynes are employed with another synthetic goal in mind, namely, in the Cadiot-Chodkiewicz reaction for the formation of symmetric or asymmetric 1,3-diynes by reaction of the haloalkyne with a terminal alkyne (Figure 13.25). Additional reagents essential for the success of this reaction are one equivalent or more of an amine and a substoichiometric amount of Cul. As with the Cacchi and Stephens-Castro coupling reactions of Section 13.3.4, a Cu-acetylide is the reactive species in the Cadiot-Chodkiewicz coupling. It is formed in step 1 of the mechanism illustrated in Figure 13.25. 

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). 

Coupling of 8-iodo-l-naphthylacetylene (80) according to the Castro method afforded two polycyclic compounds, zethrene (83) and decacyclene (84), which would be derived from intramolecular cyclization of the intermediates, 81 and 82, respectively . All other attempts to prepare 81, e.g. the Castro coupling of la with 1,8-diiodonaphthalene, led to 83 and its derivatives because of the extreme proximity of the two parallel triple bonds, within van der Waals radii . ... 

Utility of the method. The Castro coupling has been instrumental in the preparation of benzoannulenes and related macrocycles, as is shown in equations (158) and (159). 

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. - "... 

The preparation of a,p-unsaturated ketones by direct acylation of vinylcopper reagents has proven more problematic, since lithium cuprates do add to the product enones. Better results are obtained with the less reactive monovinyl copper compounds in the presence of a palladium catalyst. Alkynic ketones have been prepared by a variation of the Stephens-Castro coupling. ... 

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... 

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