Recent advances in homogeneous nickel catalysis

Abstract

Tremendous advances have been made in nickel catalysis over the past decade. Several key properties of nickel, such as facile oxidative addition and ready access to multiple oxidation states, have allowed the development of a broad range of innovative reactions. In recent years, these properties have been increasingly understood and used to perform transformations long considered exceptionally challenging. Here we discuss some of the most recent and significant developments in homogeneous nickel catalysis, with an emphasis on both synthetic outcome and mechanism.

Figure 1. Recent nickel-catalyzed Suzuki–Miyaura arylations

a, Cross-coupling of heteroaryl boronic acids (1) with heteroaryl halides (2) to form heterobiaryls (4) is a longstanding challenge. This method, employing an air-stable nickel catalyst precursor 3, provides the desired heterobiaryls in excellent yields. b, Cross-couplings developed for small-scale use are often carried out in solvents poorly suited to industrial or large-scale use. As such, the adaptation of the Suzuki–Miyaura cross-coupling to form (hetero)biaryls such as 7 using green solvents while still obtaining the products in high yield is a valuable development. dppf, 1,1’-bis(diphenylphosphino)ferrocene; cinnamyl = trans-C₆H₅CHCHCH₂-; (Het)Ar, heteroaryl; Me, methyl; THF, tetrahydrofuran; Cy, cyclohexyl.

Figure 2. Halogen alternatives used in cross-coupling reactions

a, Aryl triflates have long been used as replacements for halogens in cross-coupling reactions. Aryl nonaflates were developed later to address some of the issues encountered when working with aryl triflates, but their use is less widespread. b, The use of aryl mesylates, tosylates, and sulfamates presents many advantages over triflates and related fluorinated sulfonates due to their increased stability. c, Like sulfonate derivatives, the use of carboxylic esters, carbonates, carbamates, ethers, and silyl ethers can be advantageous in many situations. Ar, aryl; p-Tol, para-tolyl (4-methylphenyl); TMS, trimethylsilyl.

Figure 3. Milestones in cross-coupling reactions of aryl ethers and esters

a, Negishi-type, nickel-catalyzed biaryl formation from aryl ethers (8) and organomagnesium (Grignard) reagents (9). b, Suzuki–Miyaura-type, nickel-catalyzed biaryl synthesis from aryl ethers (8) and boronic esters (10). c, Suzuki–Miyaura-type, nickel-catalyzed biaryl synthesis utilizing aryl esters (11) and aryl boronic acids (12) or aryl boroxines (13). Ph, phenyl; t-Bu, tert-butyl; Et, ethyl; cod, 1,5-cyclooctadiene; i-Pr, isopropyl; Mes, 2,4,6-trimethylphenyl.

Figure 4. Reactions of benzylic alcohols and alcohol derivatives

a, Stereospecific methylation of benzylic ethers. A nickel catalyst comprising Ni(cod)₂ and rac-BINAP was found to catalyze the methylation of benzylic methyl ethers (14) to form alkyl-substituted arenes (15). A modification for the synthesis of diarylethanes was also devised, allowing the synthesis of the anti-cancer agent 16 in 69% yield and 96% ee. b, A Suzuki–Miyaura-type arylation of benzylic esters, carbonates, and carbamates. The synthesis of triarylmethanes (17) can be achieved by catalytic Ni(cod)₂ and PCy₃ or SIMes—the stereoselectivity (retention or inversion) is determined by the identity of the ligand. c, A phosphine- and carbene-free nickel catalyst was also developed, yielding inversion of the stereochemistry of benzylic pivalates (18) to provide access to diarylalkanes (22). d, Cross-coupling of free benzylic alcohols. An excess of organomagnesium reagent (21) can be added to form a magnesium alkoxide, which is then a competent coupling partner for the Kumada-type coupling with organomagnesium reagents. rac, racemic; BINAP, 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl; SIMes, (1,3-Bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene); Bu, butyl; Piv, pivaloyl.

Figure 5. Nickel-catalyzed Negishi-type cross-coupling of aromatic and aliphatic aziridines

a, Nickel-catalyzed addition of organozinc halides to styrenyl aziridines (22) occurs with incorporation of the nucleophile (23) at the substituted position of the aziridine to furnish β,β-disubstituted amines (24). b, Nickel-catalyzed addition of organozinc halides (23) to aliphatic aziridines (25) directed by the cinsyl group, which imparts a preference for addition at the less substituted position of the aziridine. Ts, (4-methyl)phenylsulfonyl; DME, 1,2-dimethoxyethane; DMA, dimethylacetamide.

Figure 6. Key representative examples of cross-coupling reactions involving oxidative addition to sp³ carbon electrophiles

a, The first example of a C_sp³–C_sp³ cross-coupling reaction using a secondary electrophile. Secondary bromides and iodides, such as 26, were coupled in a Negishi reaction with primary alkyl zinc reagents, such as 27. It was proposed the chelating PyBOX ligand (28) blocks the open coordination site needed for undesired β-hydride elimination. b, A mild (room temperature) Suzuki reaction of secondary bromides (29) and primary alkylboranes (30). Previously used bipyridyl or PyBOX ligands were unable to promote the transformation, so diamino ligand (31) was utilized. c, The first cross-coupling reaction to use an unactivated tertiary electrophile (32). In contrast to previous results, tertiary electrophiles reacted with faster rates than secondary or primary electrophiles. d, The Kumada coupling of primary alkyl bromides and iodides, and some secondary alkyl iodides, with Grignard reagents was accomplished with the Ni-pincer complex 34 with an amidobis(amine) ligand. Low temperatures allow for a wide range of functional groups (ketones, esters, etc) to be tolerated. e, The first example of a Ni-catalyzed Sonogashira reaction. β-Hydrogen-containing alkyl iodides, bromides, and chlorides could be used as the electrophile with a variety of terminal alkynes (35). 9-BBN, 9-borabicyclo[3.3.1]nonane; pin, pinacolato; glyme, bis(2-methoxyethyl) ether; Pr, propyl; Hex, hexyl.

Figure 7. Proposed mechanisms for C_sp³–C_sp³ cross-coupling

a, Mechanism proposed for Fu-type cross-coupling reactions in which ligands are typically PyBOX or similar as shown (36). A Ni(I) complex (37) undergoes transmetallation, then a radical oxidative addition of the electrophile, to eventually form a Ni(III) complex (38), which can reductively eliminate the coupled product. Nickel complexes with redox active ligands have been shown to be perhaps better thought of as the species in brackets (39, 40), in which the oxidative addition to the electrophile proceeds through ligand-centered rather than metal-centered redox. Ni(II) compounds are used as precatalysts, allowing for reactions to be set up outside of the glovebox. Reduction to Ni(I) presumably occurs prior to the beginning of the catalytic cycle via reduction of Ni(II) to Ni(0) (transmetallation/reductive elimination), then comproportionation of Ni(0)/Ni(II). b, Mechanism proposed for the C_sp³–C_sp³ Kumada cross-coupling with Ni-pincer 34. Extensive mechanistic studies have shown that a more complex bimetallic oxidative addition is operative, in which a Ni(II) complex bound to an equivalent of Grignard reagent (34’) is the active complex for the turnover-limiting transmetallation. SET, single electron transfer.

Figure 8. Asymmetric C_sp³–C_sp³ cross-coupling reactions

a, The first example of an asymmetric C_sp³–C_sp³ cross-coupling between a racemic α-bromoamide (47) and aliphatic organozinc reagent. b, Proposed mechanism for the coupling reaction. A racemic aliphatic halide adjacent to a directing group (in box) undergoes oxidative addition. Since it is proposed to proceed an unligated aliphatic radical (48) as shown in Figure 7a, the overall oxidative addition is stereoconvergent, and thus the chiral ligand on nickel dictates the stereochemistry of the product. Many classes of directing groups and transmetallating reagents have been successfully reacted, generally relying on one of the three chiral ligand classes shown in the box. Bn, benzyl; DMI, 1,3-dimethyl-2-imidazolidinone.

Figure 9. Reductive cross-coupling reactions

a, The reductive cross-coupling reaction of an aryl halide (49) with an alkyl halide (50) without the intermediacy of an organozinc or organomanganese species. Extensive mechanistic studies have suggested that this method combines both polar (aryl halide) and radical chain (alkyl halide) formal oxidative addition mechanisms. Because the oxidation state of nickel is matched to each electrophile, homodimerization is suppressed. For details on possible methods of radical chain initiation, see reference 77. b, First asymmetric acyl reductive cross-coupling. High enantioselectivities are obtained with bisoxazoline ligands such as 53. DMPU, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; DMBA, 2,6-dimethylbenzoic acid; MS, molecular sieve.

Figure 10. Selected examples of nickel-catalyzed C–H activation reactions

a, Benzoxazoles and benzothiazoles (54) are useful substrates for this nickel-catalyzed C–H activation reaction, which uses aryl esters (55) as the electrophilic coupling partners to produce (hetero)biaryls (57). This methodology was applied to the formal synthesis of muscoride A (58) to great effect. b, Nickel-catalyzed, chelation-assisted C–H activation reactions have recently been developed. These reactions rely on a directing group to facilitate addition of nickel into the C–H bond in the ortho position of a benzamide (59, 61) or into the C–H bond of an adjacent aliphatic substituent (63). dcype, 1,2-bis(dicyclohexylphosphino)ethane; OTf, triflate (trifluoromethanesulfonate); DMF, dimethylformamide.

Figure 11. Nickel-catalyzed Heck reactions

a, Coupling of aryl triflates (64) with electron-rich enol ethers (65) to obtain high selectivity for branched products, which upon acidic hydrolysis form ketones. Computational work supports a cationic Heck pathway with catalyst regeneration as turnover-limiting. b, The first Heck reaction highly selective for branched products with electronically unbiased (aliphatic) and non-chelating alkenes (67). Again, it was proposed to proceed through a cationic Ni species (69) to give high regioselectivity, and an air stable precatalyst (68) was developed to eliminate the need for air-free technique. c, Branch-selective Heck reaction for aryl electrophiles (70) with aliphatic olefins (67). Bidentate ligand 71 was key to both reactivity of aryl electrophiles and suppression of undesired isomerization. Aryl chlorides and other phenol-derived electrophiles can be utilized with the use of TESOTf, which is proposed to perform a counterion exchange in order to enter the cationic Heck pathway. TESOTf, triethylsilyl trifluoromethylsulfonate; DABCO, 1,4-diazabicyclo[2.2.2]octane.

Figure 12. Prototypical reductive coupling reactions and use of new reducing agents

a, Standard reductive coupling reaction. Oxidative cyclization of two π-components forms a nickallacycle (72), which upon formation of a Ni–H bond with a reducing agent, undergoes reductive elimination to form a new C–C σ-bond and a new C–H bond overall (73). b, Use of methanol as a mild reducing agent via the intermediacy of a hemiacetal. c, Use of isopropanol as a mild, external reducing agent, allowing for the use of air-stable Ni(II) salts as precatalysts. IPr, 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene.

Figure 13. Regiocontrol in reductive coupling reactions: two strategies

a, A tethered alkene can be used to control regioselectivity in coupling an alkyne with an aldehyde. The alkyne oxidatively adds to Ni to produce nickallacyclopropene 76. Then, by selective displacement by added phosphine ligands, or with no additive, the binding and orientation of the aldehyde is controlled to produce either linear (A) or branched (B) products. b, The steric profile of carbene ligands can be used to control the regioselectivity of an alkyne–aldehyde reductive coupling. Computational work suggests that unfavorable steric interactions between the groups on the alkyne with either the group on the aldehyde or the groups on the ligand dictate the orientation of the forming five-membered nickallacycle intermediate (shown in brackets). EtOAc, ethyl acetate; Cyp, cyclopentyl.