Sonogashira coupling

The Sonogashira coupling , sometimes also Sonogashira-Hagihara coupling , is one of the modern name reactions in organic chemistry . It is a palladium- catalyzed cross-coupling between aryl halides and terminal alkynes . It was developed in the 1970s by Kenkichi Sonogashira and Nobue Hagihara and published in 1975. It represents a further development of the Stephens-Castro coupling .

The Cacchi coupling differs from the Sonogashira coupling in terms of the starting material and reaction sequence: Instead of aryl halides, aryl triflates are used. The reaction mechanism takes place via a positively charged Pd complex and the negatively charged triflate anion instead of a neutral complex.

Overview of the Sonogashira coupling

Catalysts

This type of cross-coupling requires two catalysts , a zero-valent palladium complex and a copper halide . The palladium activates the aryl-halogen or aryl-triflate bond through oxidative addition , while the copper salt and the alkyne react in an intermediate stage to form an organic copper compound. Then the copper is exchanged for palladium. Examples are known in which the coupling also works without the copper salt.

mechanism

Mechanism of the Sonogashira coupling

The reaction requires a basic solvent, so Sonogashira and Cacchi couplings are often carried out in amines such as triethylamine , diisopropylamine or ethyl-diisopropylamine. As a result of the instability of the palladium complexes against air, the reaction is usually carried out under a protective gas atmosphere, the protective gas (e.g. argon, nitrogen) also preventing any oxygen-assisted dimerization of the alkyne used. The driving force of the reaction is the formation of the salt CuX, as this represents a thermodynamic sink and the formation is therefore energetically favorable.

Palladium cycle

• The reactive palladium (0) species is the 14 electron complex Pd (0) L ₂ A (for example, by two. Triphenylphosphane - ligand ). This reacts with the aryl halide or triflate R ¹ X in an oxidative addition to form a Pd (II) complex B.
• In the following, the rate-determining step of transmetallation of the formed complex reacts B with the copper acetylide complex to C . The copper acetylide was generated in situ in the copper cycle, releasing a copper halide (here CuX).
• The two organic ligands are trans to each other, a now following trans → cis - isomerization provides complex D .
• In the product-forming step, the product, an asymmetrically substituted alkyne , is released through reductive elimination and the Pd (0) catalyst is regenerated.

Copper cycle

• The greatest limitation of the Sonogashira coupling is the deprotonation of the terminal alkyne. This is due to the fact that the amines used (e.g. triethylamine ) have too little basicity. Presumably, deprotonation is still possible after the initial formation of the pi-alkyne complex E.
• The copper acetylide F reacts after its formation with the palladium intermediate B under regeneration of the copper halide CuX G .
• It is believed that the copper acetylide is involved in the reduction of the Pd (II) species. Here, a dialkine-PdL ₂ complex is initially formed. The Pd (0) species is then regenerated by reductive elimination and a diacetylene product is released. The Glaser coupling (coupling of two acetylenes) can therefore be viewed as a side reaction. In order to minimize the homocoupling products created by the Glaser coupling, it is important to keep the oxygen concentration as low as possible.

developments

Newer air-stable palladium complexes allow reactions under normal atmosphere. Further current research is aimed at copper-free or even solvent-free synthesis. The use of dilute aqueous ammonia solution ( c = 0.5 mol / L) as a reaction medium can be seen as a further extension .

See also

• Fukuyama reduction
• Glaser coupling
• Heck reaction
• Negishi clutch
• Stephens-Castro coupling
• Silence coupling
• Suzuki clutch

literature

• K. Sonogashira, Y. Tohda, N. Hagihara: Tetrahedron Lett. 1975, pp. 4467-4470.
• K. Sonogashira; Journal of Organometallic Chemistry . 653, 2002, pp. 46-49.
• B. Liang, M. Dai, J. Chen, Z. Yang: J. Org. Chem. 70, 2005, pp. 391-393.
• A. Mori, MSM Ahmed, A. Sekiguchi, K. Masui, T. Koike: Chemistry Letters. 2002, pp. 756-757.
• Reinhard Brückner : reaction mechanisms. 3. Edition. Spektrum, Munich 2004, ISBN 3-8274-1579-9 .
• R. Chinchilla, C. Nájera: Chem. Rev. 107, 2007, pp. 874-922.
• AG Myers, PS Dragovich: Synthesis of functionalized Enynes by Palladium / Copper-Catalyzed Coupling Reactions of Acetylenes with (Z) -2,3-Dibromopropenoic Acid Ethyl Ester: (Z) -2-Bromo-5- (Trimethylsilyl) -2- Penten-4-Ynoic Acid Ethyl Ester In: Organic Syntheses . 72, 1995, p. 104, doi : 10.15227 / orgsyn.072.0104 ; Coll. Vol. 9, 1998, p. 117 ( PDF ).
• JA Marshall, CA Sehon: Isomerization of β-Alkynyl Allylic Alcohols to Furans Catalyzed by Silver Nitrate on Silica Gel: 2-Pentyl-3-Methyl-5-Heptylfuran In: Organic Syntheses . 76, 1999, p. 263, doi : 10.15227 / orgsyn.076.0263 ; Coll. Vol. 10, 2004, p. 599 ( PDF ).

Individual evidence

1. ↑ Sonogashira, K .; Tohda, Y .; Hagiwara, N. Tetrahedron Lett. 1975 , 50 , 4467.
2. ↑ Liang, Y.-X. Xie, J.-H. Li, J. Org. Chem. , 2006 , 71, 379-381.

Web links

Sonogashira coupling in the portal for organic chemistry