The Cadiot-Chodkiewicz Coupling

Conjugated 1,3-butadiyne or longer oligoyne units are widespread structural motifs in many natural products [171] and novel functional materials [3, 167]. Their preparation is typically accompHshed by a metal-catalyzed cross-couphng of an alkynylcopper species to a haHde-terminated alkyne. While the catalytic system substantially relies on the use of Cu, the assistance of Pd is not mandatory. Either symmetric or nonsymmetric oligoynes can be made by this method, however. 

The best results for this procedure are obtained with bromoaUcynes, whereas iodoalkynes suffer from their more strongly oxidizing nature toward the Cu(I) ion, which leads to an increased formation of the by-product 72, and chloroalkynes generally show a lower reactivity. The reactivity of the terminal alkyne is similar to that described for the Sonogashira reaction. In general, arylacetylenes provide better results than alkylacetylenes. Less acidic alkynes have also been shown to produce larger quantities of the undesired 72 [182]. 

The amine base has a large effect on the efficiency of the reaction with the reactivity decreasing as follows cyclic secondary primary secondary tertiary [175, 182]. In particular, pyrrolidine provided some of the highest reported cross-coupling yields and can even facilitate the cross-couphng of iodoacetylenes and less acidic alkylacetylenes. Cosolvents, such as MeOH, EtOH, THE, DMF, and NMP, can be employed to increase solubility if necessary. 

Pd cocatalysts, which have recently been implemented into the Cadiot-Chodkiewicz reaction, gave yield improvements and, more importantly, allowed for efficient heterocoupling of iodoalkynes and chloroalkynes (Table 9.15). Upon 

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The dimerization of terminal alkynes, known as the Glaser coupling, the Eglinton coupling, and the Cadiot-Chodkiewicz coupling, is one... 

An alternative mechanism similar to that of the Cadiot-Chodkiewicz coupling ... 

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). 

Sometimes the triethylsilyl grouping is more suitable for poly-acetylene synthesis because of its greater stability, namely in the Cadiot-Chodkiewicz coupling reaction44 of a halogenoacetylene with unprotected l-phenyl-buta-l,3-diyne (39)... 

A valuable alternative is the Cadiot-Chodkiewicz Coupling which allows the preparation of asymmetric bisacetylenes. 

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 remaining steps 2 and 3 of the Cadiot-Chodkiewicz coupling and the mechanisms discussed in earlier sections of Chapter 13 show obvious analogies. Step 2 consists of the oxidative addition of the haloalkyne to a Cu(I) species. This addition may involve a transient 17 complex or it may be a one-step process. The C,C coupling occurs in step 3 as a reductive elimination and leads to the coupling product and CuBr. This step may proceed indirectly via an intermediate tt complex or directly. 

The copper(I)-catalyzed cross-coupling of a terminal alkyne and an alkynyl halide to yield diyne is known as the Cadiot-Chodkiewicz coupling. ... 

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... 

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

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. 

Heterocoupling may be accomplished via the Cadiot-Chodkiewicz coupling of terminal alkynes with haloalkynes, catalyzed by cuprous salts in the presence of aliphatic amines ... 

Although there are cases in which the use of a cuprous acetylide rather than a terminal acetylene is preferred, the use of a terminal acetylene is much easier and, as described later, more common. The reaction between a terminal alkyne and a haloalkyne using catalytic amounts of a Cu(I) salt in an amine base is known as the Cadiot-Chodkiewicz coupling (Scheme 9.23) [175]. 

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. 

For the synthesis of nonsymmetrically substituted 1,3-butadiynes the Cadiot-Chodkiewicz coupling is usually apphed [30, 31]. In this protocol a terminal alkyne is reacted with a terminal bromoalkyne derivative in the presence of a Cu(i) salt and an amine. As examples we show in Scheme 7.3 the synthesis of the l-azacydotetradeca-3,5,10,12-tetrayne derivatives 10(3)a to 10(3)f [32], 1-isopropyl-l-azacydopentadeca-3,5,ll,13-tetrayne (10(4)(c)) [33] and 1-isopropyl-l-azacydo-hexadeca-3,5,12,14-tetrayne (10(S)(c)) [33]. 

General Procedure for the Cadiot-Chodkiewicz Coupling During the Syntheses of Azacyclotetraynes 10(n)... 

The Cadiot-Chodkiewicz coupling typically proceeds under conditions which are considerably milder than Castro-Stephens reactions. Triethylsilylacetylene 74 rapidly undergoes Cadiot-Chodkiewicz coupling with alkynyl bromide 75 to generate the unsymmetrical bisalkyne 76 in nearly quantitative yield when those two reactants are treated with catalytic cuprous chloride and catalytic ammonium hydroxide in -butylamine solution. This coupling process affords one of the best entries into compounds such as 76 and is permissive of TES and larger silylated copper acetylide species because of the lower reaction temperature. ... 

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