Cadiot-Chodkiewicz Coupling Reactions

Later, Jones et al. applied this Cadiot-Chodkiewicz coupling reaction to the synthesis of triynoic acid, a fungal polyacetylene (Eq. 4.21).41... 

Gung and Dickson reported the synthesis of this molecule [54] using a three-component Cadiot-Chodkiewicz coupling reaction [55] as the pivotal step (Scheme 12.17). In this three-component reaction, diyne 112 was utilized as a bidirectional synthon and was coupled successively with bromo alkynes 111 and 113 under... 

Copper(I) derivatives of metal diynyl complexes have proven to be useful synthetic intermediates in Cadiot-Chodkiewicz coupling reactions,290 292 and similar species are implicated in coupling of metal diynyls with aryl halides under Pd/Cu catalyzed (Sonogashira) conditions241,242 and in the Cul-catalyzed coupling reactions of metal diynyl species with other metal halides.293... 

Sometimes the triethylsilyl grouping is more suitable for poly-acetylene synthesis because of its greater stability, namely in the Cadiot-Chodkiewicz coupling reaction ofa halogenoacetylene with unprotected l-phenyl-buta-l,3-diyne (59)... 

Under the conditions of the Cadiot-Chodkiewicz coupling reaction, alkylation of the reagent with l-bromo-2-phenylacctylene can be accomplished readily.4... 

Preparation of the Triacetyiene Monomers. Triacetylenes are most commonly prepared using the Cadiot-Chodkiewicz coupling reaction (11,12). Using this method each triple bond is added in a separate step. 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

Pd/Cu-catalyzed cross-coupling of organohalides with terminal alkynes. Cf. Cadiot-Chodkiewicz coupling and Castro-Stephens reaction. The Castro-Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper. 

A coupling procedure particularly suited to the synthesis of unsymmetrical diacetylenes involves the reaction of a terminal acetylene with a 1-bromo-acetylene in the presence of a catalyst consisting of a solution of copper(i) chloride in a primary amine to which small quantities of hydroxylamine hydrochloride is added (the Cadiot-Chodkiewicz coupling). 

Whereas Glaser-type oxidative coupling opens efficient synthetic pathways toward symmetrical diynes, its performance in heterocoupling is poor. The latter may be accomplished by Cadiot-Chodkiewicz coupling of terminal alkynes with 1-haloalkynes (usually 1-bromoalkynes). The reaction is conducted in the presence of an amine and catalytic amounts of a copper(I) salt. Because, in contrast with the Glaser-type reactions described above, it follows a nonoxidative reaction mechanism, oxygen is not necessary - but needs often not to be excluded (Scheme 4) [9]. 

As already mentioned, there have been few mechanistic examinations of the copper-catalyzed Cadiot-Chodkiewicz heterocoupling reaction. Kinetic studies with the less reactive chloroalkynes [11a] have led to the assumption, shown in Scheme 7, that coupling between alkynes and haloalkynes proceeds through initial formation of copper(I) acetylides, probably formed by an acetylenic activation process similar to that described above for oxidative homocouplings. Subsequently, two reaction pathways may be reasonable ... 

Scheme 9. Side-reaction observed in Cadiot-Chodkiewicz couplings (X= I, Br) [11 a].

The Ullmann reaction (Figure 13.4) represents another synthesis of substituted biphenyls. In this process an aryl iodide or—as in the present case—an aryl iodide/aryl chloride mixture is heated with Cu powder. It is presumed that under standard conditions the aryl iodide reacts in situ with Cu to form the aryl copper compound. Usually, the latter couples with the remaining aryl iodide and a symmetric biphenyl is formed. In a few instances it is also possible to generate asymmetric biaryls via a crossed Ullmann reaction. In these cases one employs a mixture of an aryl iodide and another aryl halide (not an iodide ) the other aryl halide must exhibit a higher propensity than the aryl iodide to couple to the arylcopper intermediate. It is presumed that the mechanism of the Ullmann reaction parallels the mechanism of the Cadiot-Chodkiewicz coupling, which we will discuss in Section 13.4. 

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 coupling of a terminal alkyne with a 1-bromoalkyne in the presence of a copper(i) salt and an amine base (B), referred to as the Cadiot-Chodkiewicz coupling , is of particular synthetic importance because of the facile roiite it provides to unsymmetrical polyacetylenes with an even or odd number of triple bonds (equation 10). The reaction has been reviewed and these reviews should be... 

Many reactions familiar to acetylene and polyene chemistry have been used in the synthesis of natural polyacetylenes. The longer poly-yn-ene chains are usually unstable and the tendency is to form them as late as possible in the fabrication of the molecules. Generally, terminal fragments are prepared first by taking advantage of such simple acetylenes and diacetylenes as are commercially available or relatively easily synthesized . Two reactions are then predominantly used to join these fragments the Cadiot-Chodkiewicz coupling which permits the asymmetric... 

A coupling reaction long used in acetylene chemistry is the Cadiot-Chodkiewicz coupling [112] its use in retinoid synthesis is demonstrated by the transformations depicted in Scheme 2-19 [113], The enyne precursor 169, on Cadiot-Chodkiewicz coupling with 3-bromo-2-propyn-l-ol (170) yields the diyne 171 which, by methodology long established in retinoid chemistry [114], may either be chain-elongated to dehydroretinal 172 or — via the diynal 173 — to the bis-acetylenic retinal 174. 

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