Functional Group Tolerant Kumada−Corriu−Tamao Coupling of Nonactivated Alkyl Halides with Aryl and Heteroaryl Nucleophiles: Catalysis by a Nickel Pincer Complex Permits the Coupling of Functionalized Grignard Reagents

Abstract

A nickel(II) pincer complex [((Me)NN(2))NiCl] (1) catalyzes Kumada-Corriu-Tamao cross coupling of nonactivated alkyl halides with aryl and heteroaryl Grignard reagents. The coupling of octyl bromide with phenylmagnesium chloride was used as a test reaction. Using 3 mol % of 1 as the precatalyst and THF as the solvent, and in the presence of a catalytic amount of TMEDA, the coupling product was obtained in a high yield. The reaction conditions could be applied to cross coupling of other primary and secondary alkyl bromides and iodides. The coupling is tolerant to a wide range of functional groups. Therefore, alkyl halides containing ester, amide, ether, thioether, alcohol, pyrrole, indole, furan, nitrile, conjugated enone, and aryl halide moieties were coupled to give high isolated yields of products in which these units stay intact. For the coupling of ester-containing substrates, O-TMEDA is a better additive than TMEDA. The reaction protocol proves to be efficient for the coupling of Knochel-type functionalized Grignard reagents. Thus aryl Grignard reagents containing electron-deficient and/or sensitive ester, nitrile, amide, and CF(3) substituents could be successfully coupled to nonactivated and functionalized alkyl iodides. The catalysis is also efficient for the coupling of alkyl iodides with functionalized heteroaryl Grignard reagents, giving rise to pyridine-, thiophene-, pyrazole-, furan-containing molecules with additional functionalities. Concerning the mechanism of the catalysis, [((Me)NN(2))Ni-(hetero)Ar] was identified as an intermediate, and the activation of alkyl halides was found to take place through a radical-rebound process.

Bimetallic Oxidative Addition in Nickel-Catalyzed Alkyl–Aryl Kumada Coupling Reactions

“…For example, when (bromomethyl)cyclopropane was coupled to PhMgCl, the ring-opened product 4-phenyl-1-butene was isolated as the main product. 15 This result is consistent with the formation of cyclopropyl methyl radical which undergoes rapid ring-opening rearrangement. When 3 and 4-methyl cyclohexyl iodides were coupled to PhMgCl, a constant and high diastereoselectivity was obtained regardless of the initial ratios of the cis and trans-isomers.…”

“…5,26 As reported before, the Ni(II) halide complex 1 is inactive towards alkyl halide, 12 while certain Ni(II) aryl species is active. 15 In the cage-rebound pathway (Path A), an organometallic Ni(II) aryl species activates alkyl halide to generate an alkyl radical and a formal Ni(III) halide spcies (although this Ni(III) species might be a Ni(II)-ligand cation complex).…”

“…[9][10][11] Our group has developed a nickel(II) pincer complex [( Me N 2 N)Ni-Cl] (1, Nickamine) 12 as a catalyst for the coupling of unactivated alkyl halides with alkyl, aryl, and alkynyl Grignard reagents ( Figure 1). [13][14][15][16][17] The well-defined nature of Nickamine prompted us to study the mechanism of these Kumada coupling reactions. 18,19 Recently, such study led to the discovery of a bimetallic radical oxidative addition mechanism for Ni-catalyzed alkyl-alkyl Kumada coupling.…”

Mild and Phosphine-Free Iron-Catalyzed Cross-Coupling of Nonactivated Secondary Alkyl Halides with Alkynyl Grignard Reagents

“…The following known starting materials (alkyl halides and terminal alkynes) were prepared according to the literature procedures: [2][3][4][5][6][7][8][9][10][11][12][13] …”

“…= 4.4 : 1) O Me O I 5-iodopentyl acetate [9] N O 4-(hex-5-yn-1-yl)morpholine [10] (ii) Alkynes O O 2-(hept-6-yn-1-yloxy)tetrahydro-2H-pyran [11] N 9-(hex-5-yn-1-yl)-9H-carbazole [12] OMe 1-ethynyl-4-methoxybenzene [13] SMe (4-ethynylphenyl)-(methyl)sulfane [13] O NEt 2 N,N-diethyl-4-ethynylbenzamide [13] 2-ethynyl-5-methylthiophene [13] S Me 3beta-iodo-5-cholestene [5] H H H H I…”