Nickel-Catalyzed Dicarbofunctionalization of Alkenes

Abstract

1,2-Dicarbofunctionalization of alkenes has emerged as an efficient synthetic strategy for preparing substituted molecules by coupling readily available alkenes with electrophiles and/or nucleophiles. Nickel complexes serve as effective catalysts owing to their tendency to undergo facile oxidative addition and slow β-hydride elimination, and their capability to access both two-electron and radical pathways. Two-component alkene functionalization reactions have achieved high chemo-, regio-, and stereoselectivities by tethering one of the coupling partners to the alkene substrate. Three-component reactions, however, often incorporate directing groups to control the selectivity. Only a few examples of directing-group-free difunctionalizations of unactivated alkenes have been reported. Therefore, great opportunities exist for the development of three-component difunctionalization reactions with broad substrate scopes and tunable chemo-, regio-, and stereoselectivities.

Graphical Abstract

I. INTRODUCTION

Alkenes represent one of the most useful building blocks for organic synthesis, owing to their abundance and versatile reactivity.¹ Carbofunctionalization of alkenes provides efficient access to substituted molecules from readily available alkenes by installing functional groups across their carbon–carbon double bonds.¹ The palladium-catalyzed Mizoroki–Heck reaction² and allylic alkylation reactions³ have found widespread utilities in the synthesis of natural products and pharmaceuticals (Scheme 1). Representative examples include the use of the Heck reaction in the commercial synthesis of the HIV therapeutic rilpivirine,⁴ and the application of the asymmetric allylic alkylation in the preparation of muscle relaxant flustramine derivatives.⁵ Recently, hydrofunctionalization⁶ and difunctionalization⁷ of alkenes have emerged as useful methods with some enantioselective variants.⁸ These new reactions have streamlined the preparation of the anti-inflammatory medicine naproxen⁹ and a potential inhibitor for the 5-lipoxygenase activating protein (FLAP).¹⁰

Scheme 1.

Carbofunctionalization Reactions of Alkenes

1,2-Dicarbofunctionalization of alkenes can rapidly increase molecular complexity by coupling olefins with a range of simple, readily available electrophiles and nucleophiles (Scheme 2).^1,7 Typical electrophiles include organohalides and triflates, whereas various organometallic reagents can serve as the nucleophile. 1,2-Dicarbofunctionalization with an electrophile and a nucleophile is redox-neutral, which can usually provide good chemo- and regioselectivity due to the inherent difference in reactivities of the electrophile and the nucleophile (Scheme 2A).

Scheme 2.

Overview of Nickel-Catalyzed 1,2-Dicarbofunctionalization and Mechanistic Considerations

1,2-Difunctionalization with two electrophiles requires reductants but prevents the use of air-sensitive, stoichiometric organometallic reagents, such as the Grignard and organozinc reagents (Scheme 2B). Chemo- and regioselectivity issues may arise when the reactivities of the two electrophiles are insufficiently distinct. Dicarbofunctionalizations with two organometallic reagents under oxidative conditions are rare (Scheme 2C). While several reactions have been reported with palladium catalysts, there is no example conducted with nickel catalysis.¹¹

In this Perspective, we summarize recent progress in nickel-catalyzed 1,2-dicarbofunctionalization of alkenes. The review is organized by the polarity mode of the coupling partners: the first half details redox-neutral reactions with a nucleophile and an electrophile adding to the alkene, whereas the second half describes reductive reactions coupling the alkene with two electrophiles. In each section, intramolecular, two-component reactions are discussed prior to intermolecular, three-component examples. In the end, we provide a short summary of the lingering challenges and an outlook for future directions.

A nickel-catalyzed alkene difunctionalization reaction can proceed by two types of pathways (Figure 1).¹² Reactions initiated by transmetalation of a nucleophile or oxidative addition of a C(sp²) electrophile to the nickel catalyst typically enter a classic two-electron pathway (Figure 1A): The resulting organometallic nickel species undergoes migratory insertion with an alkene to afford a metal–alkyl intermediate. Palladium-catalyzed Heck reaction invokes β-H elimination of the metal–alkyl intermediate to restore the carbon–carbon double bond. In contrast to palladium nickel-alkyl intermediates tend to cross-couple with another electrophile or nucleophile, due to the intrinsically slower β-H elimination rate relative to that of palladium.¹³

Figure 1.

Representative pathways for nickel-catalyzed alkene difunctionalization.

In addition to the classic two-electron pathway, nickel catalysts can mediate the formation of radicals from C(sp³) electrophiles and engage in radical mechanisms (Figure 1B).¹⁴ Alkene functionalization via radical addition can result in different regioselectivity compared to that obtained from migratory insertion. The presence of radical intermediates has profound implications on stereoselectivities, as formation of radicals can scramble stereocenters.¹⁵

II. REDOX-NEUTRAL INTRAMOLECULAR DICARBOFUNCTIONALIZATION

The addition of two coupling partners across the carbon–carbon double bond raises chemo- and regioselectivity issues (Scheme 2). A common strategy to facilitate difunctionalization and control the selectivity involves linking one of the coupling partners to the alkene, which compensates for the activation entropy cost and eliminates the possibility of forming regioisomers.

In an early report on intramolecular 1,2-difunctionalization, an alkyl bromide tethered to an alkene is converted in situ to the corresponding alkylzinc compound upon treatment with ZnEt₂. Upon cyclization of the alkylzinc pendent to the alkene, the intermediate proceeds to couple with another electrophile.¹⁶ The required ZnEt₂ limits the scope to substrates compatible with dialkylzinc reagents. Subsequent studies show that excellent functional group compatibility can be achieved by coupling the alkene with an organozinc halide reagent, thus preventing the use of more reactive dialkylzinc reagents (Scheme 3).

Scheme 3.

Two-Component Coupling of Olefin-Tethered Alkyl Halides with Zinc Reagents

A reported two-component difunctionalization reaction couples alkyl iodides with alkylzinc reagents by applying a Ni(pybox) (pybox = 2,6-bis(4-sec-butyl-2-oxazolinyl)pyridine) catalyst to afford pyrrolidine and tetrahydrofuran derivatives (Scheme 3A).¹⁷ Geminal-disubstituents on the carbon linkage proved essential to promote cyclization.¹⁸ An analogous cyclization of alkyl iodides employs alkyl Grignard reagents as the nucleophile.¹⁹ TMEDA (N,N,N′,N′-tetramethyl ethylenediamine) exhibits higher reactivity compared to bipyridine (bpy) and pyridine-bisoxazoline (pybox) ligands, possibly because the electron-rich (TMEDA)Ni(I) intermediate can rapidly activate C(sp³) electrophiles to form radicals.

A (terpy)NiBr₂ (terpy = 2,2′:6′,2″-terpyridine) catalyst has enabled a similar cyclization reaction that couples arylzinc reagents to the alkyl halide-tethered alkene (Scheme 3B).²⁰ The reaction tolerates a wide range of functional groups, including ketones, esters, halides, and nitriles. Base-sensitive stereocenters remain intact during the reaction. The gram-scale synthesis of a precursor to natural product (±)-collinusin has demonstrated the practical utility of this method. Radical clock experiments and analysis of the stereoselectivity, in combination with prior studies,²¹ led the authors to propose a mechanism involving radical intermediates (Scheme 3). The transmetalation of organozinc reagents to the (terpy)Ni catalyst results in a Ni(I) intermediate, which activates the alkyl halide to form a radical. Upon cyclization, the resulting radical intermediate is trapped by a (terpy)Ni(II)(X)Ar species. The resulting Ni(III) intermediate undergoes reductive elimination to form the product. This mechanism appears to be general for alkene substrates tethered with C(sp³) electrophiles.¹⁶ The involvement of radicals in the cyclization step imposes a challenge on controlling the enantioselectivity.

C(sp²) electrophiles have been shown to cyclize with tethered alkenes and couple to aryl boronic acids to afford 3,3-disubstituted oxindoles bearing all-carbon quaternary centers (Scheme 4).²² The electrophile scope includes aryl iodides, bromides, chlorides, triflates, and esters. Likely going through a Heck-type mechanism, this protocol provides a practical and sustainable alternative to the conventional palladium-catalyzed domino Heck cyclization.²

Scheme 4.

Two-Component Coupling of Olefin-Tethered Aryl Halides with Boronic Acids

Allylarene-tethered amides²³ and esters²⁴ undergo cyclization in a similar fashion to afford indanone products (Scheme 5). These substrates are conventionally inert toward low-valent palladium-mediated oxidative addition. Nickel(0) complexes are electron-rich and more reactive in activating substrates via oxidative addition.¹² The strong σ-donor ligand, SIPr (SIPr = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidine), further increases the nucleophilicity and reduces the oxidation potential of the nickel center, which proved crucial for promoting the oxidative addition of amides and esters. The coupling partners include a variety of arylboronic acids and pinacol esters, and the alkene scope comprises substituted o-allylbenzamides and o-allylbenzoates.

Scheme 5.

Two-Component Coupling of Allylarene-Tethered Esters and Amides with Boronic Acids

In contrast to the numerous examples of reactions occurring to alkenes with a pendant electrophile, there are a few reports in which the alkene is tethered to a nucleophile. In a recent example, ketones have been shown to undergo cyclization with unactivated alkenes, followed by coupling to aryl and vinyl halides, and hydroxylamine derivatives (Scheme 6).²⁵ The reaction is initiated by enolization of the ketone in the presence of Zn(TMP)₂ (TMP = 2,2,6,6-tetramethylpiperidinyl). Notably, the electron-deficient phosphine ligand was essential, likely for promoting reductive elimination.

Scheme 6.

Two-Component Coupling of Olefin-Tethered Ketones via Enolate Addition to the Alkene

Despite their significant synthetic utility, enantioselective difunctionalization reactions remain rare. An early example of an enantioselective arylalkylation features the cyclization of an olefin-tethered aryl-9-BBN (9-borabicyclo[3.3.1]nonane), followed by coupling with an alkyl bromide (Scheme 7).²⁶ Using C₂-symmetric 1,2-diamine as the chiral ligand, the reaction accomplished an efficient synthesis of the dihydrobenzofuran core of fasiglifam, investigated as an antidiabetic compound.

Scheme 7.

Enantioselective Intramolecular Arylalkylation

Photoredox-nickel dual catalysis has enabled the asymmetric keto-acylation of alkenes to afford a variety of oxindoles bearing a quaternary chiral center (Scheme 8).²⁷ The carbamoyl chloride substrate is linked to a vinylarene and can be coupled to aliphatic and aromatic aldehydes. The conditions apply a nickel-PHOX (PHOX = phosphinooxazoline) chiral catalyst in combination with tetrabutylammonium decatungstate (TBADT) as the photosensitizer. Upon photo-excitation, TBADT likely abstracts the hydrogen atom from the aldehyde to afford an acyl radical. Trapping the radical with Ni(0) forms a Ni(I)-acyl intermediate, which can undergo oxidative addition with the acyl chloride to afford a Ni(III) intermediate. Migratory insertion followed by reductive elimination delivers the oxindole product. Alkene insertion is speculated to be the enantio-determining step.

Scheme 8.

Enantioselective Keto-Acylation via Photoredox-Ni Dual Catalysis

C(sp³) electrophiles usually form radicals under nickel catalytic conditions. Formation of the stereocenter via radical cyclization hampers control of stereoselectivity. A recent report utilizes an unsubstituted alkyl chain to link the alkyl iodide and olefin moieties (Scheme 9). Upon radical cyclization, the newly formed tertiary carbon center is symmetric, preventing issues involving stereoselectivity. The resulting radical is stabilized by the adjacent boronic ester group and can be trapped by the nickel catalyst. Stereocontrol of the subsequent coupling with an organozinc reagent is dictated by the chiral diamine ligand.²⁸ Stereospecific oxidation of the boronic ester affords the corresponding chiral alcohols.

Scheme 9.

Enantioselective Intramolecular Dicarbofunctionalization of Vinyl Boronic Esters

III. REDOX-NEUTRAL INTERMOLECULAR DICARBOFUNCTIONALIZATION

Intermolecular 1,2-dicarbofunctionalization reactions of alkenes have emerged as appealing ways to prepare functionalized molecules, since an early example of a 1,2-allylmethylation of unactivated alkenes using trimethylaluminum.²⁹ Control of the chemo- and regioselectivities in three-component coupling reactions remains a preeminent challenge. Moreover, β-H elimination of the intermediate from olefin insertion can afford an unsaturated side-product. The latter impediment could be ameliorated by the intrinsically slow β-H elimination of Ni-alkyl intermediates.¹³ Directing groups proved useful in solving both issues by promoting olefin insertion, directing the regioselectivity, stabilizing the insertion intermediate, and preventing β-H elimination (Table 1).

Table 1.

Dicarbofunctionalization of Alkenes Facilitated by Directing Groups

Entry	Alkene/Directing Group	Nu	E1	Catalyst	Representative Product	Ref
1				Ni(cod)2		30
2				NiBr2		31
3				Ni(cod)2		32
4				Ni(cod)2		33
5				NiBr2		34
6				NiCl2•glyme 4,4′-diMeO-bpy		35
7						36
8				Ni(cod)2 dppm		37
9				Ni(cod)2		38
10				NiBr2•glyme		39

8-Aminoquinoline (AQ) proved effective in facilitating the difunctionalization of nonconjugated terminal and internal alkenes, using alkylzinc reagents as the nucleophile and aryl or alkyl halides as the electrophile (Table 1, entries 1 and 2).^30,31 Excess loadings of the electrophile and the nucleophile are necessary for overcoming the competing two-component cross-coupling and homodimerization reactions. The regioselectivity and the mechanism are dependent on the nature of the electrophiles (Scheme 10). Reactions with C(sp²) electrophiles involve a two-electron mechanism,³⁰ whereas those involving C(sp³) electrophiles proceed through radical intermediates.³¹ The C(sp²) electrophile first undergoes oxidative addition to the Ni catalyst; then, the resulting Ni intermediate inserts into the olefin, placing the electrophile to the position farther from AQ. In contrast, when a C(sp³) electrophile is used, transmetalation of the nucleophile occurs first, which places the nucleophile in the position farther from AQ.

Scheme 10.

Regioselective 1,2-Arylalkylation of Alkenes Directed by 8-Aminoquinoline (AQ)

Imines are effective directing groups for diarylation of vinylarenes and terminal aliphatic alkenes (Table 1, entries 3 and 4).^32,33 The latter reaction incorporates AgBF₄ or CuI as additives to in situ generate cationic Ni(II) catalysts in order to promote insertion (Table 1, entry 4).³³ After the reaction, imines can easily convert to ketones via hydrolysis.

Other directing groups include pyridine (Table 1, entry 5)³⁴ and amides (Table 1, entries 6 and 7).^35,36 β-Difluoroalkylated amines, formed from the difluoroalkylarylation of enamides, are important motifs in medicinal chemistry (Table 1, entry 6). Pyrimidine is a weakly coordinating group, which can direct the difunctionalization of allyl amines (Table 1, entry 8).³⁷ This reaction is selective for forming a 1,3-disubstitution pattern via a reversible β-H elimination and reinsertion, when aryl iodides are used as the electrophile. With alkenyl or alkynyl halides as the electrophile, the reaction forms 1,2-alkenylarylation or 2,1-alkynylarylation products.

Free carboxylic acids can serve as a directing group for the 1,2-diarylation of alkenes with aryl iodides and aryl boronates without the need of an ancillary ligand (Table 1, entry 9).³⁸ In addition, a 1,2-allylmethylation of alkenes is achieved by using an allyl electrophile and dimethylzinc as the nucleophile (Table 1, entry 10).³⁹ This reaction recruits a variety of weakly coordinating heterocycle directing groups, such as saccharin, phthalimide, pyridone, pyrazole, triazole, tetrazole, and benzoxazole. These conditions do not require ancillary ligands to the nickel catalyst.

Recent efforts have endeavored to avoid directing groups as these moieties can mitigate the substrate scope and practical applications of difunctionalization reactions (Table 2). Diastereoselective diarylation of vinylarenes with aryl bromides and arylboron reagents affords triarylated products in high yields (Table 2, entry 1).⁴⁰ This reaction can be carried out on gram-scale. The mechanistic proposal invokes a Ni(0)/Ni(II) catalytic cycle. Notably, the use of 0.1 equiv of (Bpin)₂, in the presence of KOEt, is essential to reduce NiCl₂ to a Ni(0) species.

Table 2.

Redox-Neutral Intermolecular Dicarbofunctionalization of Alkenes

Entry	Alkene	Nu	E1	Catalyst/Ligand	Representative Product	Ref
1				NiCl2		40
2				NiBr2 or (Ph3P)2NiCl2		41
3				Ni(cod)2		42
4				NiCl2•glyme dtbbpy		43
5				[lr]/NiCl2•glyme dtbbpy		44
6				Ru(bby)3Cl2•6H2O NiCl2•6H2O dtbbpy		45
7				Ni(cod)2		46

An alkylarylation of vinylarenes combines alkyl halides and arylzinc reagents to form 1,1-diarylalkane products (Table 2, entry 2).⁴¹ This reaction has been applied as the final step to assemble a potential inhibitor for the 5-lipoxygenase activating protein (FLAP).¹⁰ Recently, the scope of the electrophile has been extended to include α-halocarbonyl compounds (Table 2, entry 3).⁴² Mechanistic studies reveal that the reaction is initiated by a Ni(0) species, stabilized by the solvent and the alkene, which activates the alkyl halide via SET to generate an alkyl radical as the turnover-limiting step. Addition of the alkyl radical to the olefin affords a benzylic radical, which combines with the Ni(I)-X intermediate. The resulting Ni(II)-X species undergoes transmetalation with ArZnX, followed by reductive elimination (Scheme 11).

Scheme 11.

Regioselective Alkylarylation of Vinylarenes

Radicals, frequently formed upon activation of alkyl halides, are key intermediates in Ni-catalyzed cross-coupling reactions. Novel methods to generate radicals have been applied toward 1,2-dicarbofunctionalization and to expand the substrate scope. Redox-active esters serve as the electrophile in the difunctionalization of α,β-unsaturated esters (Table 2, entry 4).⁴³ Alkyl oxalates have become common radical precursors under photoredox conditions, and the resulting organic radicals have shown to couple with vinyl and allylic esters (entry 5).⁴⁴ The reaction utilizes the common [Ir{dF(CF₃)₂ ppy}₂(bpy)]PF₆ photocatalyst with blue LED light irradiation in combination with NiCl₂·glyme and 4,4′-di-tert-butyl-2,2′-dipyridyl. A Ru(bpy)₃Cl₂·6H₂O/nickel dual catalytic condition has enabled the arylalkylation of vinyl esters with aryl iodide and alkyl silicates with blue light irradiation (Table 2, entry 6).⁴⁵ The relative stoichiometry of the substrates proved to be critical, as a slight excess of alkene and alkyl silicate prevents the direct cross-coupling of the aryl iodide.

An intermolecular carboacylation of norbornene uses acetylamides as the acyl source (Table 2, entry 7).⁴⁶ The reaction is initiated via oxidative addition of the amide C–N bond to Ni(0), followed by insertion to the alkene. Triarylboranes, generated in situ from the corresponding tetraarylborates, serve as the nucleophile.

Vinylboronates are appealing and useful substrates. The capability of boryl groups stabilizing adjacent radicals can exert excellent control of regioselectivity.⁴⁷ The boryl products are useful cross-coupling partners and can be readily oxidized to give alcohols. Alkylarylation reactions of vinylboronates exploit photoredox-nickel dual catalysis (Scheme 12).^48–50 These reactions proceed through a common mechanism: the photocatalyst activates the alkyl substrate to generate a radical intermediate, which may then add to vinylboranates. The high regioselectivity is dictated by the formation of an α-boryl radical. Trapping the radical with a nickel catalyst sets the stage for subsequent coupling with an aryl halide. Alkyl radical precursors include alkyltrifluoroborates,⁴⁸ carboxylic acids,⁴⁹ and alkyl halides,⁵⁰ which are activated by photocatalysts, [Ir{dF(CF₃)₂ ppy}₂(bpy)]PF₆,⁴⁸ and 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN).^49,50 The use of alkyl halides as the other coupling partner necessitates a reductant, tetramethylethylenediamine (TMEDA) (see further in Section V).⁵⁰

Scheme 12.

Regioselective Alkylarylation of Vinyl Boronic Esters

The enantioselectivity of the intermolecular dicarbofunctionalization reaction is particularly difficult to control with only few examples having been reported.⁵¹ The 1,2-dialkylation and 1,2-arylalkylation of alkenyl boronic acid pinacol esters (BPin) take advantage of α-boryl radical stabilization (Scheme 13).²⁸ In the presence of NiBr₂·glyme and a chiral diamine ligand, alkyl zinc halides and tertiary alkyl halides are added across a vinyl boron reagent in good yield and enantioselectivity. Following oxidation of pinacol borane easily generates chiral secondary alcohol products with a retention of the stereochemistry

Scheme 13.

Asymmetric 1,2-Dicarbofunctionalization of Vinylboranes

IV. REDUCTIVE INTRAMOLECULAR DICARBOFUNCTIONALIZATION WITH ELECTROPHILES

The use of stoichiometric organometallic reagents has limitations in cost, sustainability, and reagent availability. Additionally, organometallic reagents, such as Grignard or organozinc reagents, tend to interfere with acidic or electro-philic functional groups.⁵² Reductive alkene 1,2-dicarbofunctionalization reactions with electrophiles have emerged, which avoid the need for organometallic nucleophiles. A major challenge of this strategy is to achieve chemo- and regioselectivity, as the two electrophiles can exhibit indistinguishable reactivity. Two-component coupling by tethering one of the electrophiles to the olefin has been applied as a perfunctory solution to this issue.

An early example of two-component reductive difunctionalization incorporates an alkene substrate tethered to an alkyl bromide and couples it with an aryl iodide. The reaction requires a [Ni⁰·2EC·Py] (EC = ethyl crotonate, Py = pyridine) catalyst, generated by mixing NiCl₂ with Zn, pyridine, and EC (Scheme 14).⁵³ The diastereoselectivity is consistent with the prediction of the Beckwith–Houk model.⁵⁴ This reaction can be applied to prepare diverse spiroketals,⁵⁵ trans-tetrahydronaphtho[2,3-β]furans,⁵⁶ and a podophyllum lignan core.⁵⁷ An analogous arylalkylation occurs with alkenes, to which aryl bromides are tethered.⁵⁸ In addition, redox active N-hydroxyphthalimide esters can be used as an alkyl source in place of alkyl bromides.⁵⁹

Scheme 14.

Two-Component Reductive Dicarbofunctionalization

A relevant intramolecular reductive dicarbofunctionalization of alkenes with pendant alkyl bromide electrophiles employs the common precatalyst NiBr₂·glyme and the ligand 1,10-phenanthroline (phen) (Scheme 15).⁶⁰ These mild conditions are compatible with a wide range of bromo-alkene substrates and aryl, heteroaryl, and alkyl bromide electrophiles to afford substituted carbo- and heterocycles. A mechanistic study on this system rules out the “radical chain” mechanism⁶¹ but favors a “sequential reduction” pathway.⁶² The reduction of (phen)Ni(II) intermediates to Ni(I) species by Zn is determined to be the turnover-limiting step. The sequence and mechanism of electrophile activation control the chemo-selectivity for cross-coupling over homocoupling of each electrophile. The C(sp²) and the C(sp³) electrophiles are activated by different Ni intermediates via different pathways. The sterically accessible (phen)Ni(I)–Br selectively activates aryl bromides via two-electron oxidative addition, whereas alkyl bromides are activated by the more electron-rich (phen)Ni(I)–Ar to afford radicals.

Scheme 15.

Mechanism of Two-Component Reductive Dicarbofunctionalization of Alkenes

Several examples of asymmetric arylalkylation,⁶³ arylalkenylation,⁶⁴ and diarylation⁶⁵ have been reported to form indanes, indolines, and dihydrobenzofurans bearing quaternary carbon centers (Table 3). A common feature of the substrate is a C(sp²) electrophile tethered to an alkene. The other suitable coupling partners include alkyl bromides^63a (entry 1), benzyl chlorides (entry 2),^63b vinyl triflates (entry 3),^64a vinyl bromides (entry 4),^64b gem-difluoroalkenes (entry 5),^64c and aryl bromides (entry 6),⁶⁵ and the alkene scope includes both activated and unactivated alkenes. Effective chiral ligands include bioxazolines (biOx), pyridine-oxazolines (pyrOx), and phosphinooxazolines (PHOX).

Table 3.

Asymmetric Two-Component Dicarbofunctionalization of Alkenes

Entry	Tethered Alkene	E1	Catalyst/Ligand	Representative Product	Ref
1					63a
2					63b
3					64a
4					64b
5					64c
6					65

The mechanism of the diarylation of enamides (Table 3, entry 6) has been investigated.⁶⁵ Control experiments ruled out the participation of arylzinc intermediates. The reaction is proposed to be initiated by the oxidative addition of the aryl bromide to a Ni(0) species to afford an aryl-Ni intermediate (Scheme 16). The subsequent 5-exo cyclization is irreversible and likely determines the stereoselectivity. The Ni(II) alkyl intermediate is further reduced, followed by oxidative addition of the aryl bromide substrate and reductive elimination.

Scheme 16.

Proposed Mechanism of Intramolecular Enantioselective Diarylation of Enamides

Enantioselective carboacylation has been developed by tethering aryl carbamoyl chlorides to styrenes, which are coupled to primary and secondary alkyl iodides or benzyl chlorides (Scheme 17).⁶⁶ This cascade cyclization/cross-coupling reaction enables the construction of diverse oxindoles bearing a quaternary stereocenter. Mechanistic investigations suggest that the Ni(II)-mediated intramolecular migratory insertion serves as the enantio-determining step.

Scheme 17.

Enantioselective Reductive Carboacylation of Alkenes

Existing enantioselective dicarbofunctionalization reactions are initiated by oxidative addition of the olefin-tethered C(sp²) electrophile and involves the insertion of the aryl-Ni intermediate into the alkene as a common enantio-determining step. C(sp³) electrophiles usually form radicals upon activation by Ni catalysts. Therefore, there have been no examples of asymmetric alkylarylation for an alkene with a pendent C(sp³) electrophile, likely due to the difficulty of controlling the stereoselectivity of radical cyclization.

V. REDUCTIVE INTERMOLECULAR 1,2-DICARBOFUNCTIONALIZATION

Intermolecular reductive 1,2-dicarbofunctionalization reactions are underdeveloped owing to the challenge of controlling chemo- and regioselectivity for two electrophiles with similar reactivity. Directing groups have been used to overcome this issue. The first example of reductive arylalkylation was developed with allylic acetates, amines, and nitriles (Scheme 18).⁶⁷ The alkene scope was later expanded to simple olefins, 1,4- and 1,5-dienes, and enynes, which undergo cascade cyclization and coupling.⁶⁸ While the reaction is compatible with a variety of aryl iodides, the alkyl coupling partner is limited to tertiary alkyl iodides. Control experiments and computational studies reveal that oxidative addition of the aryl iodide to the low-valent Ni catalyst is followed by reduction of the Ni(III)-aryl species by TDAE (TDAE = tetrakis-(dimethylamino)ethylene) to afford a Ni(I)-aryl intermediate. The Ni(I)-aryl species subsequently activates the alkyl iodide to form a radical. Radical addition to the alkene at the terminal position forms a secondary radical intermediate. Trapping of the intermediate by the Ni(II)-aryl species generates a Ni(III) intermediate that can undergo reductive elimination. This sequence of electrophile activation is consistent with the experimental study on a two-component reductive difunctionalization reaction.⁶²

Scheme 18.

Intermolecular Reductive Alkylarylation of Alkenes and the Mechanistic Proposal

The directing group strategy has been used to develop a 1,2-acyl-fluoroalkylation and an arylalkylation of alkenes. The former reaction is effective for alkenes tethered to chelating groups including esters, carbonates, sulfonates, and phosphates (Scheme 19A).⁶⁹ The alkyl radical, generated from alkyl iodides, adds to the alkene, which then coordinates to Ni and proceeds to couple with the acyl chloride. The pendent, weak chelating group plays a vital role in facilitating the capture of the alkyl radical intermediate by the nickel species, thereby controlling the chemo- and regioselectivity. Primary and secondary alkyl electrophiles are ineffective substrates, and reactions are limited to terminal olefins. By using the 8-aminoquinoline directing group, the scope of difunctionalization has been expanded to aryl-alkylation, alkenyl-alkylation, and dialkylation of internal alkenes (Scheme 19B).⁷⁰

Scheme 19.

Intermolecular Reductive Dicarbofunctionalization by Using Directing Group

Three-component, intermolecular asymmetric alkene difunctionalization is rare and challenging. The first example of asymmetric 1,2-diarylation couples vinylarenes with bromoarenes to afford α,α,β-triarylated ethane scaffolds, which are prominent in biologically active molecules (Scheme 20).⁷¹ The reaction utilizes NiBr₂·glyme as the precatalyst, (S,S)-sec-BubiOx as the chiral ligand, and Zn as the reductant. An N-oxyl radical additive, ABNO (9-azabicyclo[3.3.1]nonane N-oxyl), substantially improves the enantioselectivity. Preliminary data suggests that ABNO may serve as a ligand to Ni. Several observations serve as evidence for the formation of a radical intermediate at the benzylic position, which reversibly binds to the Ni catalyst. It is conceivable that the reductive elimination is the enantio-determining step. This reaction, however, is limited to the addition of two identical aryl groups across the double bond, and the alkene scope is limited to vinylarenes.

Scheme 20.

Asymmetric Reductive Diarylation of Vinylarenes

The first example of an asymmetric three-component difunctionalization using two different electrophiles was recently reported (Scheme 21).⁷² Allyl esters undergo 1,2-fluoroalkylarylation, coupling with aryl and heteroaryl halides and perfluoroalkyl iodides. The enantioselectivity is induced by chiral biOx ligands, and the indole 3-carboxylate ester plays a crucial role in achieving high yields and the enantioselectivity. Control experiments reveal that the reaction is likely initiated by the addition of the perfluoroalkyl radical to the allyl ester, followed by cross-coupling with the aryl halide. The use of electron-deficient arenes appears to improve the enantioselectivity.

Scheme 21.

Asymmetric Reductive 1,2-Fluoroalkylarylation of Allyl Esters

An analogous asymmetric three-component coupling adds tertiary iodides and aryl iodides or bromides across the carbon–carbon double bond of vinyl amides, boronic esters, and phosphates (Scheme 22).⁷³ The reaction proceeds at room temperature in the presence of an organic reductant, TDAE. An alkyl Ni(III) intermediate ligated with (l)-isoleucine derived biOx is proposed based on DFT calculations. This intermediate is stabilized by the coordination of amides or other coordinating groups on the alkene, which contribute to defining the stereochemical outcome.

Scheme 22.

Asymmetric Reductive Dicarbofunctionalization of Alkenes

CONCLUSION AND OUTLOOK

Nickel-catalyzed 1,2-dicarbofunctionalization of alkenes has emerged as an efficient strategy to build substituted structural motifs. Common reaction conditions employ commercially available nickel precursors and nitrogen-containing ligands. The conditions are generally mild and do not require high temperatures. Maintaining an inert atmosphere for the reactions, however, is necessary for those involving air-sensitive organometallic nucleophiles and radical intermediates. Reactions involving nucleophiles and C(sp²) electrophiles often proceed by two-electron pathways, whereas C(sp³) electrophiles likely invoke radical intermediates.

Intramolecular, two-component difunctionalization reactions have achieved notable success with a broad substrate scope. By tethering a coupling partner to the alkene, intramolecular reactions limit the number of possible regioisomers and hence improve the selectivity. As a result, intramolecular, two-component dicarbofunctionalization reactions have found applications in the synthesis of a series of biologically active molecules. Significant challenges remain in intermolecular, three-component coupling reactions in achieving chemo-, regio-, and stereoselectivities with a broad scope of substrates, due to the multiple numbers of possible products. Consequently, rarely does organic synthesis leverage these reactions as intermediate steps.

Regioselectivity issues have limited most intermolecular reactions to electronically biased alkenes or ones with directing groups. Directing groups have been used to promote functionalization of unactivated alkenes and have permitted the control of regioselectivity, but the removal of directing groups is not always straightforward and could cause limitations in its application. Only a few numbers of difunctionalization reactions have been discovered for unactivated alkenes without directing groups, and their synthetic applications are yet to be explored. Chemo- and regioselectivities remain challenging for reductive dicarbofunctionalization with two electrophiles, due to their inherent similar reactivity. Recent mechanistic studies reveal that C(sp²) and C(sp³) electrophiles can be activated by different nickel species via two-electron and radical pathways, respectively.⁶² This finding provides a basis for distinguishing the reactivity of different electrophiles and achieving chemoselectivity, and has already been practiced in reaction methodology.

Enantioselectivity has been achieved for intramolecular difunctionalization of alkenes tethered to C(sp²) nucleophiles and electrophiles. Migratory insertion of the C(sp²) moiety into the alkene is commonly proposed to be the enantio-determining step. In contrast, when the alkene substrate is tethered to a C(sp³) coupling partner, enantioselectivity becomes difficult, due to the formation of radical intermediates that undergo cyclization, which does not involve a chiral catalyst.

It was only until recently that asymmetric intermolecular difunctionalization reactions have been discovered. They all invoke open-shell nickel intermediates and a radical pathway. Radical intermediates, formed from C(sp³) electrophiles, present both challenges and opportunities for controlling stereoselectivity via new stereocontrol mechanisms. The coordination of a radical intermediate to the nickel center could serve as the enantio-determining step. With stabilized radicals, it has been proposed that the trapping of radical by the nickel center could be reversible.⁷¹ This process can scramble the stereocenter, making the stereoselectivity of prior steps inconsequential. In this scenario, the enantio-determining step could thus be deferred to the following reductive elimination.

Challenges also remain in the scope of alkenes. Most difunctionalization reactions are performed on terminal alkenes. The reactivity of internal alkenes is intuitively lower, if alkene coordination to the metal center is required prior to insertion. This limitation could be overcome by invoking the addition of radicals to the alkene. Furthermore, the difficulty to control the regio- and stereo-selectivity may have also hampered the development of difunctionalization reactions of internal alkenes.