Kumada synthesis

Synthesis of Poly(p-phenylene) 24 by Using Kumada Coupling58... 

Kumada-Corriu Reactions Investigated in Micro Reactors Organic synthesis 47 [OS 47] Reaction between 4-bromoanisole and phenylmagnesium bromide [2]... 

It was not until Cazin and co-workers introduced the well-defined dimer complex [Pd( J,-Cl)(Cl)(SIPr)]2 that the Kumada-Tamao-Corriu cross-coupling between severely sterically hindered partners was pursued, allowing the synthesis of tri- and tetra-orf/io substituted biaryls [81] (Scheme 6.20). 

Kumada s use of a ferrocene moved away from the C2-symmetrical motive, as planar chirality can result from the two ferrocene rings having different substituents. The development of this class of ligand is well documented [5, 125-127]. The best-known uses of these ligands are for reductions of carbon-heteroatom multiple bonds, as in the synthesis of the herbicide, Metolachlor [128, 129]. 

Organomagnesium reagents, which can serve as the nucleophiles in the Kumada coupling, are easy to make and many of them are commercially available. Even though some Kumada reactions can be run at room or lower temperature, many functional groups are not tolerant of Grignard reagents. Nonetheless, in the synthesis of thienylbenzoic acid 24, the carboxylic acid moiety did survive the reaction conditions [25],... 

In the direct synthesis of aryl terminal alkynes via Pd-catalyzed cross-coupling of aryl halides with ethynylmetals, formation of diarylethynes is one of the potential side reactions. Indeed, the Kumada coupling of 2-iodo-5-methylthiophene (29) with ethynylmagnesium chloride gave the desired 2-ethynyl-5-methylthiophene (30) in only 35% yield, along with 24% of bis(5-methyl-2-thienyl)ethyne (31) [29], The high propensity for H-Mg exchange reaction to occur was blamed for the diarylethyne formation. 

Advantage has been taken of the aforementioned observations in the synthesis of a terthiophene natural product, arctic acid (147) [123]. Pd-catalyzed carbonylation of bromobisthiophene 25, obtained from the Kumada coupling of 2-thienylmagnesium bromide and 2,5-dibromothiophene, gave bithiophene ester 144, which was converted to iodide 145 by reaction with iodine and yellow mercuric oxide. Subsequent propynylation of 145 was then realized using the Sonogashira reaction with prop-l-yne to give bisthienyl alkyne 146, which was subsequently hydrolyzed to 5 -(l-propynyl)-2,2 -bithienyl-5-carboxylic acid (147), a natural product isolated from the root of Arctium lappa. 

Low reactive aryl chlorides are converted to the respective organomagnesium species in excellent yields through transition metal catalysis using 2 mol% FeCU (4-6, equation 3). Alternatively, a safe and reproducible method for activation of aryl chlorides or bromides 7 uses microwave irradiation (equation 4). In a synthesis of a novel HIV-1 protease inhibitor, microwave irradiation was essential to generate the starting arylmagnesium halide as well as to promote the subsequent Kumada coupling reaction. ... 

For a review, sec Hayashi Kumada. in Morrison Asymmetic Synthesis, vol. 5 Academic Press New York, 1985. pp. 147-169. Sec also Cross Kellogg J. Chem. Soc.. Chem. Commun. 1987, 1746 Iida Yamashita Bull. Chem. Soc. Jpn. 1988, 61. 2365. 

K. Tamao and M. Kumada, in The Chemistry of the Metal-Carbon Bond. The Use of Organometallic Compounds in Organic Synthesis (F. R. Hartly, ed.) Wiley London, 1987. 

T. Hayashi and M. Kumada, Asymmetric Coupling Reactions, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 5, Chap. 5, Academic Press, New York, 1985 J. C. Fiaud, Mechanisms in Stereo-Differentiating Metal-Catalyzed Reactions. Enantioselective Palladium-Catalyzed Allylation, in A. F. Noels, M. Graziani, and A. J. Hubert, eds., Metal Promoted Selectivity in Organic Synthesis, p. 107, Kluwer Academic, Dordrecht, 1991. 

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