Cadiot-Chodkiewicz coupling synthesis

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. ... 

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

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. 

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). 

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... 

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)... 

Fig. 16.33. Pd(0)-catalyzed alkynylation of a copper acetylide with a silylated ethynyl iodide in a two-step synthesis of a monosilylated 1,3-butadiyne. If the same copper acetylide is alkynylated with higher alkynyl iodides and subsequently heated with potassium carbonate in toluene, monoalkylated 1,3-butadiynes result - The Pd-free alkynylation of a copper acetylide ("Cadiot-Chodkiewicz coupling") is shown in Figure 16.9.

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. 

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. 

Synthesis of Natural Polyacetylenes.—Bohlmann and Weber have reported the synthesis of racemic samples of four polyacetylenic enol-ethers (43), (44), (45), and (46), isolated earlier from Anaphalis species (Scheme 2). The acetonide from the 3-hydroxydihydropyrone (40) was first converted into chloride (41) which with sodamide produced the acetylenic alcohol (42). Successive reaction (Cadiot-Chodkiewicz coupling) of bromohepta-1,3,5-triyne with (42) and treatment with base gave the cis- and /m jr-(43) enol-ethers, which reacted with thionyl chloride to produce cw-(44) and trans- A5)y respectively. Epoxidation of (45) then gave (46). In the same publication. 

Protecting groups are clearly required if these reactions are to be employed in terminal acetylene synthesis since, with few exceptions [10], attempts to carry out both Glaser and Cadiot-Chodkiewicz couplings with acetylene itself or with bromoacetylene lead to, extensive and, uncontrollable polymerization, whilst cuprous acetylide itself is inert under the conditions of the Castro reaction. 

Aryl-acetylene synthesis, Cf. Cadiot-Chodkiewicz coupling. 

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]. 

Scheme 7.3. Synthesis of nonsymmetrically substituted cyclic butadiynes 10(n) using Cadiot-Chodkiewicz coupling as the key step, (a) Cul, pyrrolidine (35-66%), (b) H2SO4, H20/Me0H (67-84%), (c) PBrs, pyridine/Et20 (38-62%), (d) K2CO3,...

The two reactions described above can be applied for the synthesis of symmetrical few-acetylenes only. Unsymmetrical bis-acetylenes can be prepared by using the Cadiot-Chodkiewicz reaction. For that method a terminal alkyne 1 is reacted with a bromoalkyne 8 in the presence of a copper catalyst, to yield an unsymmetrical coupling product 9 ... 

Scheme 12.17. Synthesis of minquartynoic acid using a three-component Cadiot-Chodkiewicz double cross-coupling, by Cung and Dickson [54], TBS = t-butyldimethylsilyl,...

Much of the new chemistry on the coupling of alkynyl halides has dealt mostly with applications of known methods. The Cadiot-Chodkiewicz-type coupling reactions (i.e. terminal acetylene coupling with alkynyl halides) have formed the cornerstone of synthesis of acetylenic retinoids (i.e. 9)58. 

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