Nickel-catalyzed Hydroalkylation Research Articles

Regio- and Diastereoselective Synthesis of Trisubstituted Alkenes Through Hydroalkylation of Alkynyl Boronamides.

Hydroalkylation of alkynes is a powerful method for alkene synthesis. However, regioselectivity has been difficult to achieve in transformations of internal alkynes hindering applications in the synthesis of trisubstituted alkenes. To overcome these limitations, we explored using boryl groups as versatile directing groups that can control the regioselectivity of the hydroalkylation and subsequently be replaced in a cross-coupling reaction. The result of our exploration is a nickel-catalyzed hydroalkylation of alkynyl boronamides that provides access to a wide range of trisubstituted alkenes with high regio- and diastereoselectivity. The reaction can be accomplished with a variety of coupling partners, including primary and secondary alkyl iodides, α-bromo esters, α-chloro phthalimides, and α-chloro boronic esters. Preliminary studies of the reaction mechanism provide evidence for the hydrometalation mechanism and the formation of alkyl radical intermediates.

Regiodivergent and Enantioselective Synthesis of Cyclic Sulfones via Ligand-Controlled Nickel-Catalyzed Hydroalkylation.

Cyclic sulfones have demonstrated important applications in drug discovery. However, the catalytic and enantioselective synthesis of chiral cyclic sulfones remains challenging. Herein, we develop nickel-catalyzed regiodivergent and enantioselective hydroalkylation of sulfolenes to streamline the synthesis of chiral alkyl cyclic sulfones. The method has broad scope and high functional group tolerance. The regioselectivity can be controlled by ligands only. A neutral PYROX ligand favors C3-alkylation whereas an anionic BOX ligand favors C2-alkylation. This control is kinetic in origin as the C2-bound Ni intermediates are always thermodynamically more stable. Reactivity study of a wide range of relevant Ni intermediates reveal a NiI/NiIII catalytic cycle with a NiII-H species as the resting state. The regio- and enantio-determining step is the insertion of this NiII-H species into 2-sulfolene. This work provides an efficient catalytic method for the synthesis of an important class of organic compounds and enhances the mechanistic understanding of Ni-catalyzed stereoselective hydroalkylation.

Understanding the Reaction Mechanism of Ni-Catalyzed Regio- and Enantioselective Hydroalkylation of Enamines: Chemoselectivity of (Bi-oxazoline)NiH.

This density functional theory study explores the detailed mechanism of nickel-catalyzed hydroalkylation of the C═C bond of N-Cbz-protected enamines (Cbz = benzyloxycarbonyl) with alkyl iodides to give chiral α-alkyl amines. The active catalyst (biOx)NiH, a chiral bioxazoline (biOx)-chelated Ni(I) hydride, exhibits chemoselectivity that favors single electron transfer to the alkyl iodide over C═C hydrometalation with the enamine. This generates an alkyl radical and a Ni(II) intermediate, which takes up the enamine substrate CbzNHCH═CH2CH3 via a regio- and enantioselective C═C insertion into the NiII-H bond. The resulting Ni(II) alkyl complex combines with the alkyl radical, forming a Ni(III) intermediate, from which the alkyl-alkyl reductive elimination delivers the chiral amine product. The regioselectivity arises from a combination of orbital and noncovalent interactions, both of which are induced by the Cbz group. Thus, Cbz plays an additional role in controlling regioselectivity. The enantioselectivity stems from the differing distortion energies of CbzNHCH═CH2CH3. The reductive elimination is the rate-determining step (ΔG⧧ = 18.7 kcal/mol). In addition, the calculations show a noninnocent behavior of the biOx ligand induced by the insertion of CbzNHCH═CH2CH3 into the Ni-H bond of (biOx)NiH. These computationally gained insights can have implications for developing new Ni(I)-catalyzed reactions.

Two birds with one stone: asymmetric construction of vicinal C(sp3) centres by nickel-catalyzed hydroalkylation of alkenes

Two birds with one stone: asymmetric construction of vicinal C(sp3) centres by nickel-catalyzed hydroalkylation of alkenes

Theoretical studies on substrate-controlled selectivity of nickel-catalyzed hydroalkylation of 1,3-dienes

The detailed mechanism of the substrate-controlled selectivity in the nickel-catalyzed hydroalkylation of 2-substituted 1,3-diene has been investigated.

Mechanism of nickel-catalyzed hydroalkylation of branched 1,3-dienes

With the development of algorithms and theoretical chemistry, quantum chemical calculations have been used to explain and predict various chemical experiments. The hydroalkylation of conjugated olefins catalyzed by nickel is an important type of organic chemical reaction, and its mechanism has always been the focus of organic chemists. In this paper, a hydroalkylation reaction developed by the Mazet research group was studied in detail by means of density functional theory (DFT), and a possible mechanism model of the reaction was obtained. In this context, the attractive regioselectivity of the reaction was explored and rationally explained.

Nickel-Catalyzed Hydroalkylation of Trifluoromethylalkenes

Nickel-Catalyzed Hydroalkylation of Trifluoromethylalkenes

Enantio- and Diastereoselective Construction of Vicinal C(sp3) Centers via Nickel-Catalyzed Hydroalkylation of Alkenes

Enantio- and Diastereoselective Construction of Vicinal C(sp3) Centers via Nickel-Catalyzed Hydroalkylation of Alkenes

Photoredox- and Nickel-Catalyzed Hydroalkylation of Alkynes with 4-Alkyl-1,4-dihydropyridines: Ligand-Controlled Regioselectivity.

Dual photoredox- and nickel-catalyzed hydroalkylation of terminal alkynes with 4-alkyl-1,4-dihydropyridines under visible light irradiation to afford Markovnikov- or anti-Markovnikov-type alkylated alkenes in good-to-high yields has been achieved, in which the regioselectivity of the products was effectively controlled by coordination ligands for nickel species. Using [NiCl2 (dtbbpy)] as a catalyst led to the formation of Markovnikov-type products, whereas using NiCl2 ⋅ 6 H2 O led to the formation of anti-Markovnikov-type products.

Theoretical study of nickel-catalyzed hydroalkylation of 3-pyrrolines: Origin of ligand-controlled regioselectivity

Nickel catalysts have shown unique ligand control of regioselectivity in the hydroalkylation of 3-pyrrolines. The (2-(5-bromopyridin-2-yl)-3a,8a-dihydro-8H-indeno[1,2-d]oxazole) ligand (L1) produces a C2-alkylated pyrrolidine, while the (4-benzyl-2-(6-methylpyridin-2-yl)-4,5-dihydrooxazole) ligand (L2) delivers a C3-alkylated pyrrolidine. We have explored the mechanism and origin of the ligand-controlled regioselectivity with density functional theory (DFT) calculations. The calculation results show good agreement with the experimental results for the regioselectivity. The hydroalkylation reactions of 3-pyrrolines with the two different ligands occur via completely different mechanisms, neither of which is via the traditional route proposed by experimental research. These mechanistic rationales are supported by several related experimental observations in ref. 40. For the L1 ligand, the regioselectivity is determined by two competing transition states, a β-hydride elimination transition state and a C–C reductive elimination transition state. For the L2 ligand, radical coupling and β-H elimination steps are responsible for the regioselectivity. The bulky L1 ligand facilitates the β-hydride elimination step and thus leads to the C2-alkylated pyrrolidine product. The less bulky L2 ligand prefers radical coupling step and thus results in the C3-alkylated pyrrolidine product.

Ni-catalyzed hydroalkylation of olefins with N-sulfonyl amines

Hydroalkylation, the direct addition of a C(sp3)–H bond across an olefin, is a desirable strategy to produce valuable, complex structural motifs in functional materials, pharmaceuticals, and natural products. Herein, we report a reliable method for accessing α-branched amines via nickel-catalyzed hydroalkylation reactions. Specifically, by using bis(cyclooctadiene)nickel (Ni(cod)2) together with a phosphine ligand, we achieved a formal C(sp3)–H bond insertion reaction between olefins and N-sulfonyl amines without the need for an external hydride source. The amine not only provides the alkyl motif but also delivers hydride to the olefin by means of a nickel-engaged β–hydride elimination/reductive elimination process. This method provides a platform for constructing chiral α-branched amines by using a P-chiral ligand, demonstrating its potential utility in organic synthesis. Notably, a sulfonamidyl boronate complex formed in situ under basic conditions promotes ring-opening of the azanickellacycle reaction intermediate, leading to a significant improvement of the catalytic efficiency.

Nickel-catalyzed hydroalkylation of 1,3-dienes with malonates using a homoallyl carbonate as the 1,3-diene and hydride source

The use of a malonate nucleophile in the transition metal-catalyzed hydroalkylation of 1,3-dienes remains immature. Herein, we report the nickel-catalyzed hydroalkylation of 1,3-dienes with malonates using a homoallyl carbonate as the 1,3-diene and hydride source. A broad range of homoally carbonates and malonate derivatives were well tolerated under a Ni/DPEphos catalyst system, providing the corresponding 1,2-hydroalkylation products in 40–94% yields with excellent regioselectivity (32 examples). We also suggested the possible reaction mechanism for the nickel-catalyzed hydroalkylation of in situ generated 1,3-dienes with malonates.

Chiral Alkyl Amine Synthesis via Catalytic Enantioselective Hydroalkylation of Enecarbamates.

Chiral alkyl amines are omnipresent as bioactive molecules and synthetic intermediates. The catalytic and enantioselective synthesis of alkyl amines from readily accessible precursors is challenging. Here we develop a nickel-catalyzed hydroalkylation method to assemble a wide range of chiral alkyl amines from enecarbamates (N-Cbz-protected enamines) and alkyl halides with high regio- and enantioselectivity. The method works for both nonactivated and activated alkyl halides and is able to produce enantiomerically enriched amines with two minimally differentiated α-alkyl substituents. The mild conditions lead to high functional group tolerance, which is demonstrated in the postproduct functionalization of many natural products and drug molecules, as well as the synthesis of chiral building blocks and key intermediates to bioactive compounds.

Nickel-Catalyzed Hydroalkylation of Terminal Olefins with Linear N-Sulfonyl Amines

Nickel-Catalyzed Hydroalkylation of Terminal Olefins with Linear <i>N</i>-Sulfonyl Amines

Nickel-Catalyzed Hydroalkylation of Olefins

Nickel-Catalyzed Hydroalkylation of Olefins

Nickel-catalyzed hydroalkylation and hydroalkenylation of 1,3-dienes with hydrazones.

Transition-metal-catalyzed hydrofunctionalization of 1,3-dienes is a useful and atom-economical method for constructing allylic compounds. Although substantial progress on hydroalkylation of dienes with stabilized carbon nucleophiles has been made, hydroalkylation of dienes with unstabilized carbon nucleophiles has remained a challenge. In this article, we report a protocol for nickel-catalyzed hydroalkylation of dienes with hydrazones, which serve as equivalents of alkyl carbon nucleophiles. In addition, we developed a protocol for hydroalkenylation of dienes with α,β-unsaturated hydrazones, providing a new method for the synthesis of 1,4-dienes. These hydroalkylation and hydroalkenylation reactions feature mild conditions and a wide substrate scope, and the utility of the reaction products is demonstrated by the preparation of an activator of soluble guanylate cyclase.