James Sanderson

Fluorinated organic molecules are of interest in fields ranging from medicinal chemistry to polymer science. Described herein is a mild, convenient, and versatile method for the synthesis of compounds bearing a perfluoroalkyl group attached to a tertiary carbon atom by using an alkyl–alkyl cross-coupling. A nickel catalyst derived from NiCl₂⋅glyme and a pybox ligand achieves the coupling of a wide range of fluorinated alkyl halides with alkylzinc reagents at room temperature. A broad array of functional groups is compatible with the reaction conditions, and highly selective couplings can be achieved on the basis of differing levels of fluorination. A mechanistic investigation has established that the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) inhibits cross-coupling under these conditions and that a TEMPO–electrophile adduct can be isolated.

A new pairing: A mild, convenient, and versatile method for the synthesis of compounds bearing a perfluoroalkyl group on a tertiary carbon atom is described. The title reaction results in the coupling of a wide range of fluorinated alkyl halides with alkylzinc reagents at room temperature. A broad array of functional groups are compatible with the reaction conditions, and preliminary mechanistic studies are discussed. DMA=N,N-dimethylacetamide.

Reported herein is an unprecedented ligand-free copper-catalyzed cross-coupling of alkyl-, aryl-, and alkynylzinc reagents with heteroaryl iodides. The reaction proceeds at room temperature for the coupling of primary, secondary, and tertiary alkylzinc reagents with heteroaryl iodides without rearrangement. An elevated temperature (100 °C) is required for aryl–heteroaryl and alkynyl–heteroaryl couplings.

Simply copper: Primary, secondary, and tertiary alkylzinc reagents couple with heteroaryl iodides in the presence of ligand-free CuI without complications arising from β-hydride elimination and rearrangement. The reactions can be extended to the couplings of aryl- and alkynylzinc reagents as well. DMF=N,N-dimethylformamide.

A Rh^I-catalyzed three-component reaction of tert-propargyl alcohol, diazoester, and alkyl halide has been developed. This reaction can be considered as a carbene-involving sequential alkyl and alkynyl coupling, in which C(sp)C(sp³) and C(sp³)C(sp³) bonds are built successively on the carbenic carbon atom. The Rh^I-carbene migratory insertion of an alkynyl moiety and subsequent alkylation are proposed to account for the two separate CC bond formations. This reaction provides an efficient and tunable method for the construction of all-carbon quaternary center.

All on C: A sequential Rh^I-catalyzed alkyl and alkynyl coupling on a carbene successively establishes a C(sp)C(sp³) and then a C(sp³)C(sp³) bond on the original carbenic carbon center. The reaction results in the formation of an all-carbon quaternary center in high efficiency. A rhodium–carbene migratory insertion is proposed as the key step in this transformation.

The flow metalation of various arenes and heteroarenes involving an in situ trapping with metal salts (ZnCl₂⋅2 LiCl, MgCl₂, CuCN⋅2 LiCl, LaCl₃⋅2 LiCl) under very convenient conditions (0 °C, 40 s) is reported. The resulting Mg, Zn, Cu, or La organic species are trapped with various electrophiles in high yields. In several cases, unusual kinetically controlled regioselectivities are obtained. All these flow metalations can be scaled up simply by extending the reaction time and without further optimization. The reaction scope of such flow metalations is considerably broader than that of the corresponding batch procedures.

Flow makes the difference: In situ trapping transmetalations in which functionalized arenes or heterocycles are mixed with metal salts proceed at 0 °C within 40 s in a continuous flow apparatus. Subsequent batch quenching of the resulting Mg, Zn, Cu, or La organic species with various electrophiles proceeds in high yields (see example).

The influence of the metal on the nucleophilic reactivities of indenyl metal compounds was quantitatively determined by kinetic investigations of their reactions with benzhydrylium ions (Ar₂CH⁺) and structurally related quinone methides. With the correlation equation log k₂=s_N(N+E), it can be derived that the ionic indenyl alkali compounds are 10¹⁸ to 10²⁴ times more reactive (depending on the reference electrophile) than the corresponding indenyltrimethylsilane.

Different worlds: Kinetic investigations with reference electrophiles show that a reaction with an electrophile, which would proceed within milliseconds with indenyl lithium, would require much more than the age of the universe with the corresponding organosilicon compound. Met=metal.

Cobalt(II)-catalyzed C(sp²)O cross-coupling between aryl/heteroaryl alcohols and vinyl/aryl halides in the presence of Cu^I has been achieved under ligand-free conditions. In this reaction, copper plays a significant role in transmetalation rather than being directly involved in the CO coupling. This unique Co/Cu-dual catalyst system provides an easy access to a library of aryl–vinyl, heteroaryl–styryl, aryl–aryl, and heteroaryl–heteroaryl ethers in the absence of any ligand or additive.

Raring to Co: The first application of a cobalt catalyst in the intermolecular C(sp²)O cross-coupling of aromatic alcohols has been achieved in presence of a copper cocatalyst as transmetalating agent. This unique Co/Cu-dual catalyst system provides easy access to a library of aryl–vinyl, heteroaryl–styryl, aryl–aryl, and heteroaryl–heteroaryl ethers in the absence of any ligand or additive.

Asymmetric catalytic multistep reactions enable the formation of structurally complex compounds from simple starting materials. Enantioselective Cu-catalyzed 1,4-additions of Grignard reagents to Michael acceptors form reactive chiral enolates. We show here that these chiral enolates react in a one-pot fashion with naked carbenium ions, such as tropylium, 1,3-benzodithiolium, and dianisylmethylium ions. The corresponding products were obtained in good yields, with enantioselectivities up to 96% ee and high diastereomeric purities.

Grignard reagents are probably the best organometallics to develop large-scale eco-friendly cross-couplings compatible with the requirements of sustainable development. This account aims to highlight some reactions having an interesting industrial potential and gives the personal point of view of the authors on some attractive fields of research in this area.

An efficient, green and first catalytic process has been developed for the direct synthesis of amides from readily available petroleum by-products (methylarenes) and amines using an iron catalyst. In this new catalytic reaction, the methyl group of the methylarene is oxidized to the corresponding aldehyde through non-directed CH oxidation followed by its oxidative amidation with N-chloroamine, yielding the carboxylic amide. Oxidation with an iron catalyst, tert-butyl hydroperoxide (TBHP) as sole oxidant, the synthesis of amides under mild reaction conditions and the utilization of methylarenes as starting material make this methodology novel and environmentally benign.

The reaction scope of iron- and cobalt-catalyzed cross-coupling reactions in the presence of isoquinoline (quinoline) in the solvent mixture tBuOMe/THF has been further investigated. Various 2-halogenated pyridine, pyrimidine, and triazine derivatives were arylated under these mild conditions in excellent yields. The presence of isoquinoline allows us to perform Fe-catalyzed cross-coupling reactions between 6-chloroquinoline and aryl magnesium reagents. Furthermore, it was found that the use of 10 % N,N-dimethylquinoline-8-amine increases the yields of some Co-catalyzed cross-coupling reactions with chloropyridines bearing electron-withdrawing substituents.

Iron out your coupling! The use of iron and cobalt catalysts in a combination with only 10 % isoquinoline represents a practical method for the cross-coupling reactions of various 2-halogenopyridines, -pyrimidines, and -triazines, as well as 6-halogenoquinolines with functionalized aryl or heteroaryl Grignard reagents (see scheme).

The nickel-catalyzed alkyl–alkyl cross-coupling (CC bond formation) and borylation (CB bond formation) of unactivated alkyl halides reported in the literature show completely opposite reactivity orders in the reactions of primary, secondary, and tertiary alkyl bromides. The proposed Ni^I/Ni^III catalytic cycles for these two types of bond-formation reactions were studied computationally by means of DFT calculations at the B3LYP level. These calculations indicate that the rate-determining step for alkyl–alkyl cross-coupling is the reductive elimination step, whereas for borylation the rate is determined mainly by the atom-transfer step. In borylation reactions, the boryl ligand involved has an empty p orbital, which strongly facilitates the reductive elimination step. The inability of unactivated tertiary alkyl halides to undergo alkyl–alkyl cross-coupling is mainly due to the moderately high reductive elimination barrier.

Boron makes a difference: The mechanisms of alkyl–alkyl cross-coupling and alkyl halide borylation catalyzed by nickel complexes have been investigated (see scheme; Hex=hexyl, B₂pin₂=bis(pinacolato)diboron). The differences between the two mechanisms have been elucidated.

1+1=3: By combining the exceptional reactivities of cyclic hypervalent iodine reagents and iron catalysts, Sharma and Hartwig achieved the azidation of CH bonds with unprecedented efficiency and selectivity. The late-stage introduction of azides into complex bioactive molecules will greatly facilitate the synthesis of analogues and accelerate the discovery of new chemical entities.