The Kumada Reaction

Grignard reagents have been generated from sluggish aryl chlorides and bromides by use of controlled MW irradiation in a safe, productive, and reproducible 

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Based on these results, conditions for alkyl-Sonogashira coupling reactions were developed. Primary alkyl halides reacted with terminal alkynes catalyzed by 5 mol% of complex 24a and Cul in the presence of substoichiometric amounts of Nal for bromides or Bu4NI for alkyl chlorides (entry 29) [73]. The latter serves to catalyze the in situ generation of more reactive alkyl iodides under the reaction conditions. The internal alkyne products were isolated in 57-89% yield. The Sonogashira coupling can also be combined to the Kumada reaction described above. a,o)-Chloroalkyl bromides underwent the Kumada coupling first selectively... 

The Kumada reaction has been used for the preparation of polyfunctionalized pyridines. In one example, Grignard reagent 82 was coupled to pyridyl derivative 81 using palladium catalysis to afford 83 in excellent yield [28]. 

The Grignard reagent of 2-chloro thiophene underwent the Kumada reaction with 2,6-dichloropyridine 84 to produce the monosubstituted pyridine 85. Mixed heteroarene 86 was afforded when 85 was allowed to react with the Grignard derived from, V-methyl-2-bromoindole [29]. 

Scheme 2.18 Catalytic cycle for the Kumada reaction catalyzed by Nickamine (compound 45).

The Kumada reaction offers a more direct approach to the desired products compared with Suzuki and Negishi reactions. However, the Kumada reaction shows poorer functional group compatibility. When the substrates tolerate the background reactivity of a Grignard reagent, the Kumada reaction is a powerful tool to construct new carbon-carbon bonds. 

The Kumada Reactions Nickel-Catalyzed Cross-Coupling with Grignard Reagents... 

The Kumada reaction was employed for the synthesis of dendralenes, cross-conjugated alkenes, which show interesting reactivity (Scheme 2.20). The products even include the labile [3]dendralene 2.56 which has a half-life of just 10 h at 25 °C. 

The Kumada reaction has become the most frequently used method in the synthesis of various types of thiophenes. Since its mechanism is basically valid also for other reactions catalyzed by transition metals, it will be elucidated more thoroughly [69, 70]. The catalytic cycle is depicted in Fig. 3. 

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