What Is Cadiot-Chodkiewicz Coupling?
The Cadiot-Chodkiewicz coupling reaction is a fundamental method for synthesizing symmetric and unsymmetric diynes and polyynes. This reaction allows for the production of a wide range of aromatic and aliphatic diacetylenes, yielding 1,3-diynes in high amounts using affordable Cu as a catalyst under mild conditions.
In 1955, Cadiot and Chodkiewicz reported the first copper (I)-catalyzed coupling of 2-methyl-but-3-yn-2-ol 2 with bromoalkyne 1 to give 1,3-diyne 3 (Scheme A). The cross-coupling reaction between terminal alkyne 4 and haloalkyne 5 in the presence of Cu(I) salts is now known as the Cadiot-Chodkiewicz coupling reaction, named after P. Cadiot and W. Chodkiewicz (Scheme B).
In principle, the synthesis of asymmetric diynes can be carried out with any combination of terminal alkynes and bromoalkynes. However, in the coupling of (A) and (B), when the (B) type coupling is carried out, the bulky trialkylsilyl (triethylsilyl, tert-butyldimethylsilyl and triisopropylsilyl) alkynes can be coupled with high yield, while the trimethylsilyl cannot obtain the coupling product. Moreover, the 30% (volume fraction) n-butylamine aqueous solution used for coupling is less alkaline than the commonly used 70% ethylamine aqueous solution.
Fig 1. The classical work and general representation of the Cadiot–Chodkiewicz reaction. [1]
Moreover, some studies have shown the enhanced application of Pd as a co-catalyst in combination with copper(I) salt. Additionally, the use of a nickel catalyst alongside copper in the coupling of aromatic terminal alkynes with aromatic halides without a ligand has been reported. One of the benefits of this coupling is its compatibility with various substrates and functional groups.
Reaction Mechanism of Cadiot-Chodkiewicz Coupling
Limited research has been conducted on the mechanistic understanding of the Cadiot-Chodkiewicz reaction. The accepted Cu-catalyzed mechanism typically involves the deprotonation of the terminal alkyne by a base to form Cu(I) acetylide I. The oxidative addition of I with haloalkyne II results in the formation of a bis alkynyl copper species III. The reductive elimination of III leads to the synthesis of the desired 1,3-diyne while regenerating the copper catalyst.
Fig 2. The mechanism of Cu-catalyzed Cadiot-Chodkiewicz coupling. [1]
Application Examples of Cadiot-Chodkiewicz Coupling
- Example 1: This reaction is sensitive to the substrate. Phenyl and hydroxyalkyl groups attached to the alkyne can promote the coupling reaction. The coupling of terminal silyl protected alkynes can be achieved through a one-bottle deprotection-coupling method, which was used in the total synthesis of the highly anticancer active compound (S)-(E)-15,16-dihydrominguartynoic acid. [2]
- Example 2: Phil C. Knutson et al. developed a useful complement to the Cadiot-Chodkiewicz alkyne-alkyne cross-coupling to synthesize 1,3-diynes from in situ generated volatile brominated alkynes. The method requires in situ elimination from a dibromoolefin precursor and immediate exposure to copper-catalyzed conditions, thus avoiding the hazards of volatile brominated alkynes. [3]
- Example 3: Xiangdong Li et al. proposed a gold-catalyzed Cadiot-Chodkiewicz cross-coupling strategy of terminal alkynes with alkynyl hypervalent iodine reagents for the highly selective synthesis of asymmetric 1,3-diynes. The reaction has the advantages of high selectivity, high efficiency, mild reaction conditions, broad substrate scope, and good functional group compatibility. [4]
Fig 3. Synthetic examples via Cadiot-Chodkiewicz coupling.
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References
- Sankaran Radhika, et al. Org. Biomol. Chem., 2019(17), 9081-9094.
- Benjamin W. Gung, et al. J. Org. Chem., 2004, 69(10), 3488-3492.
- Phil C. Knutson, et al. Org. Lett., 2018, 20(21), 6845-6849.
- Xiangdong Li, et al. Angewandte Chemie International Edition, 2017, 56(24), 6994-6998.
