Keywords

1 Introduction

The development of various types of new reactions that form carbon–carbon bonds with high efficiency and selectivity is one of the most important goals in modern synthetic organic chemistry. As described in previous chapters, the catalytic cross-coupling reactions excel in regio- and stereoselectivities. They also enjoy a wide coverage of substrates; therefore, they have been recognized as powerful methods for carbon–carbon bond construction. Furthermore, as described in Chap. 7, various inert carbon electrophiles such as organic chlorides, as well as mesylates and tosylates converted from a hydroxyl group, have become available as coupling partners in this catalyst system.

However, these cross-couplings have not been able to utilize unreactive electrophiles for the construction of any hybridized carbon–carbon bonds. Thus, the commonly used carbon electrophiles had to have π-electrons, e.g., aryl, alkenyl (sp2), or alkynyl (sp) carbons. As described in Chap. 2, the nickel- and palladium-catalyzed cross-coupling reactions proceed according to the catalytic cycle, including: oxidative addition, transmetalation, and reductive elimination. Among these steps, oxidative addition easily occurs because the carbon electrophile’s π-electrons can coordinate to the metal centers to generate the π-complex 1, which undergoes oxidative addition to form complex 2 (Scheme 8.1). Therefore, when the substrates with an sp2 or an sp-hybridized reaction site are used as carbon electrophiles, the cross-coupling reactions occur under much milder conditions.

Scheme 8.1
scheme 1

Oxidative addition of aryl halides through the generation of the π-complex 1

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In sharp contrast to the molecules bearing π-bonds, the alkyl electrophiles bearing the β-hydrogens have scarcely been used as carbon electrophiles in the catalytic cross-coupling reactions. The main reasons for the poor success of cross-coupling reactions of the alkyl halides are as follows: (1) the saturated carbon electrophiles have no π-electron that can coordinate to the metal center and (2) the weak electronic attraction of the sp3 hybridized carbons at a carbon–halogen bond results in slow oxidative addition. Furthermore, when the alkyl electrophiles have β-hydrogens, the d orbital of the transition metals and the C–H σ-bond have an electronic interaction; β-hydrogen elimination in the alkyl complexes occurs smoothly to give the hydrido complexes 3 along with olefins derived from oxidative addition (Eq. 8.1).

(8.1)

Therefore, before the desired cross-coupled products are formed, the thermodynamically favored, rapid β-hydrogen elimination competitively proceeds after either oxidative addition (path A) or transmetalation (path B), generating olefin by-products (Scheme 8.2). Although a large amount of research has been elucidated for the widely applicable and reliable cross-coupling reactions of aryl and alkenyl electrophiles, development of the cross-coupling reactions of the alkyl electrophiles as synthetic methods was thus forsaken for a long time.

Scheme 8.2
scheme 2

Catalytic cycles involving alkyl electrophiles

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However, in the late 1990s, growing concern over this undeveloped field in the catalytic cross-coupling reactions of alkyl electrophiles prompted examination and advancement from the viewpoints of development of new ligands and the use of unprecedented transition-metal catalysts. Gradually, new cross-coupling reactions including the alkyl groups as coupling partners were reported, by retarding β-hydrogen elimination. This chapter presents the cross-coupling reactions of the alkyl electrophiles, focusing on representative examples found after 2000.

2 Kumada–Tamao–Corriu Coupling

The first Kumada–Tamao–Corriu coupling of alkyl halides was the reaction with Grignard reagents catalyzed by silver, reported by Kochi and Tamura in the early 1970s [1–3]. Although a few similar reactions catalyzed by transition metals such as copper and nickel had been reported over the ensuing 20 years, chemical yields of the products were unsatisfactory [4, 5].

After many years of effort, in 1986 Castle and Widdowson finally reported that the desired cross-coupled products could be obtained from the reactions of primary and secondary alkyl iodides with alkyl magnesium bromides in high yields, in the presence of PdCl2(dppf) [6]. In 1998 Koten and Cahiez reported Kumada–Tamao–Corriu cross-couplings of primary, secondary, and tertiary alkyl Grignard reagents with n-alkyl bromides caused by a paramagnetic manganese (II) catalyst 4 bearing a tridentate ligand and CuCl as a co-catalyst (Eq. 8.2) [7].

(8.2)

In addition, in 2000 Cahiez reported the cross-coupling reactions of alkyl halides with alkyl or aryl magnesium reagents by using the copper catalysts (Eq. 8.3) [8]. When alkyl magnesium compounds were used as nucleophiles in this reaction, N-methylpyrrolidone (NMP) solvent promoted the reaction; on the contrary, when the aryl magnesium reagents were employed, NMP suppressed the reaction progress. Unfortunately, secondary and tertiary alkyl halides and a series of alkyl chlorides were found not to be applicable to this reaction.

(8.3)

Terao and Kambe reported in 2002 the nickel-catalyzed Kumada-Tamao-Corriu coupling reactions of alkyl Grignard reagents with alkyl chlorides or bromides (Eq. 8.4) [9]. This reaction protocol also enabled the application to alkyl tosylates. A small catalyst loading with the assistance of 1,3-butadiene as the ligand gave the corresponding cross-coupled products in good to excellent yields.

(8.4)

Moreover, Terao and Kambe showed that the 1,3-butadiene ligand stabilized the active species and promoted reductive elimination. The proposed reaction mechanisms are shown in Scheme 8.3. First, NiCl2 is reduced by R1MgX, and then two molar equivalents of 1,3-butadiene react with the generated Ni(0) species to form the bis(π-allyl)nickel complex 5. This complex 5, which is inert toward oxidative addition of the alkyl halides, selectively reacts with Grignard reagents to afford the nickelate complex 6. The subsequent oxidative addition of alkyl halides and reductive elimination give the desired cross-coupled products. In addition, in 2003 Terao and Kambe also reported the cross-coupling reactions of alkyl tosylates or bromides with alkyl magnesium reagents, accelerated by the combination of the palladium catalyst with the 1,3-butadiene ligands [10].

Scheme 8.3
scheme 3

Ni-catalyzed alkyl-alkyl coupling by using 1,3-butadiene ligand

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Very recently, several examples of Kumada–Tamao–Corriu coupling reactions catalyzed by nickel have been reported using Cp*CH2PPh2 (Cp* = C5Me5) as the ligand (Eq. 8.5) [11]. Also, the pincer-type tridentate amido ligands of the nickel (II) complex 7 have been recently described (Eq. 8.6) [12].

(8.5)
(8.6)

An example with palladium catalysis (involving the palladium(II) acetate-tricyclohexylphosphine catalyst system) was reported by Beller in 2002 utilizing the alkyl-aryl-type Kumada–Tamao–Corriu coupling reactions (Eq. 8.7) [13].

(8.7)

In addition, Beller reported for the first time in 2003 the analogous Kumada–Tamao–Corriu coupling reactions using the palladium naphthoquinone catalysts 8 ligated with N-heterocyclic carbene (NHC) ligands (Eq. 8.8) [14].

(8.8)

Recently, much attention has been paid to the development of the cross-coupling reactions catalyzed by the less expensive, ubiquitous transition-metal catalysts rather than nickel and palladium as the catalysts. Since the report by Kochi in 1971 of iron(III) chloride-catalyzed Kumada–Tamao–Corriu coupling [15], satisfying results using the iron catalysts had not been obtained for decades. But, Fürstner found in 2002 that acetylacetonato iron could be an effective catalyst for the Kumada–Tamao–Corriu coupling of aryl chlorides with alkyl magnesium reagents [16].

After this pioneering work, a great deal of research on the Kumada–Tamao–Corriu coupling promoted by the iron catalysts has led to utilization of this chemistry by many other researchers in the recent years [17–24]. Representative synthetic examples of such are shown in Scheme 8.4.

Scheme 8.4
scheme 4

Fe-catalyzed Kumada-Tamao-Corriu coupling of alkyl electrophiles

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In addition to the iron catalysts, cobalt and vanadium complexes were found by Oshima to be highly effective for catalysis of the alkyl-aryl Kumada–Tamao–Corriu coupling of the alkyl electrophiles with aryl magnesium reagents (Scheme 8.5) [25–27].

Scheme 8.5
scheme 5

Co- and V-catalyzed Kumada-Tamao-Corriu coupling of alkyl electrophiles

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As described herein, it seems that the catalysts for Kumada–Tamao–Corriu coupling reactions of the alkyl electrophiles are no longer limited to palladium and nickel. In the iron-catalyzed reactions the anionic iron complex is postulated to be the active species, while in the reactions catalyzed by cobalt and vanadium a radical mechanism has been proposed. Therefore, these catalytic cycles might proceed in different manners from the established palladium and nickel-catalyzed cross-couplings. However, the aryl nucleophiles applicable to the cobalt- and vanadium-catalyzed cross-coupling reactions are limited to Grignard reagents, significantly limiting the types of coupled products due to poor functional group tolerance. It is noteworthy that the catalytic activities were found to be superior to palladium and nickel in some of the reaction systems mediated by cobalt and vanadium.

3 Negishi Coupling

Tucker and Knochel reported the first account of Negishi coupling using alkyl halides in 1993; this work dealt with the reactions of alkyl iodides and dialkyl zinc reagents, mediated by a stoichiometric amount of [Cu(CN)Me2(MgCl2)] [28]. Two years later, using a nickel catalyst, Knochel also reported the alkyl–alkyl Negishi coupling of the alkyl zinc reagents with alkyl iodides functionalized with a double bond in the 4- or 5-positions [29]. However, because severe substrate limitations were observed in these reactions, they were not generally exploited.

Finally, Knochel found in 1998 the more preparative Negishi coupling reactions of alkyl iodides (sans double bonds) with organozinc reagents, by adding styrene additives with an electron-withdrawing trifluoromethyl group, under nickel catalysis (Eqs. 8.9, 8.10) [30–32].

(8.9)
(8.10)

In 2003, Zhou and Fu reported Negishi coupling reactions with alkyl electrophiles by using a palladium catalyst ligated with tricyclopentylphosphine (Eq. 8.11) [33]. The reaction efficiently took place with unactivated primary alkyl iodides, bromides, chlorides, and even tosylates. In addition, it was clarified that the addition of N-methylimidazole (NMI) promoted transmetalation from zinc to palladium and that the product yields were dramatically improved.

(8.11)

In addition, Fu has also succeeded in an extension of these reactions to include the cross-coupling reactions of secondary alkyl bromides and iodides (Eq. 8.12) [34]. These newer reactions smoothly proceed at room temperature with the aid of the nickel catalyst bearing the bis(oxazolinyl)pyridine (pybox) ligand 11.

(8.12)

Recently, Organ further expanded the range of the substrate scope in Negishi coupling reactions of alkyl electrophiles involving alkyl chlorides, mesylates, and tosylates by the palladium complexes (PEPPSI) 12 having N-heterocyclic carbene (NHC) and 3-chloropyridine as auxiliary ligands (Eq. 8.13) [35].

(8.13)

Lipshutz reported reactions of alkyl halides at room temperature in water using the organozinc reagents generated in situ from zinc-diamine complexes and the commercially available amphiphile polyoxyethanyl α-tocopheryl sebacate (PTS); these reactions were catalyzed by palladium complex 13 having bulky and electron-rich phosphine ligands (Eq. 8.14) [36].

(8.14)

The Negishi coupling reactions of alkyl electrophiles catalyzed by the other transition metals (rather than palladium and nickel) have been recently exploited. For instance, in 2005 Nakamura et al. reported the alkyl-aryl Negishi coupling of primary and secondary alkyl halides with aryl zinc reagents, catalyzed by iron(III) chloride in high to excellent yields (Eq. 8.15) [37].

(8.15)

Very recently, Takagi et al. found that the rhodium complexes ligated with 3-diphenylphosphino-2-(diphenylphoshino)methyl-2-methylpropyl acetate 14 (a tripodal ligand) showed excellent catalytic activity in the alkyl-aryl Negishi coupling reactions. This provides a facile and useful synthetic method for polyfunctionalized alkylbenzenes (Eq. 8.16) [38].

(8.16)

4 Migita–Kosugi–Stille Coupling

Migita–Kosugi–Stille coupling reactions of alkyl halide electrophiles were reported by Fuchikami in 1996, using PdCl2(PPh3)2 as the catalyst [39]. In these reactions, alkyl iodides substituted with an electron-deficient fluorine atom in the β-position reacted with organotin compounds. However, the yields of the coupled products were not satisfactory and heavy catalyst loading was necessary. Later, research disclosed that electron-rich alkyldimonophosphine ligands (rather than simple trialkylphosphines) are effective, especially for Migita–Kosugi–Stille coupling of alkyl electrophiles in the palladium-phosphine catalyst system. In 2001, Fuchikami et al. reported Migita–Kosugi–Stille-type coupling reactions of alkynyl stannanes with alkyl iodides bearing a fluorine atom in the γ- or δ-position, catalyzed by Pd(PPh3)4. It has been hypothesized that the oxidative addition of these fluorinated alkyl halides generates an alkyl palladium complex, which is stabilized by an internal coordination of fluorine to the metal center, suppressing the undesired β-hydrogen elimination [40].

Fu reported in 2003 that Migita–Kosugi–Stille coupling reactions of tributyl stannanes with primary alkyl bromides bearing substituents in the ω-position smoothly occurred at room temperature by using cyclohexyl di pyrrolidinyl phosphine as the ligand in the presence of tetramethylammonium fluoride as an activator (Eq. 8.17) [41].

(8.17)

In 2006, the palladium-catalyzed methylation of alkenyl stannanes was carried out by incorporating a short-lived 11C-labeled methyl group into biologically significant methylated alkenes with the aim of synthesizing a positron emission tomography (PET) tracer (Eq. 8.18) [42]

(8.18)

5 Suzuki–Miyaura Coupling

The first palladium-catalyzed alkyl–alkyl-type coupling reactions of primary alkyl iodides with alkyl boron compounds were reported by Suzuki and Miyaura in 1992 (Eq. 8.19) [43]. These reactions can be catalyzed by Pd(PPh3)4; 9-BBN (9-borabicyclononane)-containing alkyl boron compounds were employed as the substrates, but only primary alkyl iodides were successfully applicable to this protocol.

(8.19)

Subsequently, Charette reported Suzuki–Miyaura coupling reactions in 1996 of aryl and alkenyl boronic acids with the alkyl electrophile iodo cyclopropane under palladium catalysis (Eq. 8.20) [44]. However, the range of applicable alkyl electrophiles was found to be rather limited.

(8.20)

Since 2000, many innovative alkyl–alkyl Suzuki–Miyaura coupling reactions have been reported by Fu et al. In 2001, they succeeded in the coupling reactions of primary alkyl bromides with alkyl boron compounds using potassium phosphate as the base and tricyclohexylphosphine as the ligand of a palladium catalyst (Eq. 8.21) [45]. Because of the mild conditions, this reaction has tolerance of a wide variety of substituents, with not only the double and triple bonds, but also the polar functional groups such as esters, nitriles, and amides.

(8.21)

In 2002, Fu discovered that the palladium-catalyzed Suzuki–Miyaura coupling of primary alkyl chlorides with alkyl boron compounds can proceed with cesium hydroxide as the base (Eq. 8.22) [46]. Those reaction conditions are also compatible with a variety of functional groups, including nitriles and amines.

(8.22)

Subsequently, Fu reported Suzuki–Miyaura coupling reactions of primary alkyl tosylates (Eq. 8.23) [47] and bromides (Eq. 8.24) [48] with alkyl boron reagents, based on the palladium catalyst systems involving the ligand PtBu2Me under various reaction conditions (bases, solvents, etc.); the structures of the alkyl palladium complexes formed by oxidative addition of alkyl bromides to Pd(PtBu2Me)2 were determined by X-ray structural analyses.

(8.23)
(8.24)

In 2004, Caddick and Cloke reported the alkyl–alkyl-type Suzuki–Miyaura coupling reactions of primary alkyl bromides with alkyl boron compounds by using the palladium catalyst with N-heterocyclic carbene ligand 15 (Fig. 8.1) [49]. However, yields of the coupled products were below 60% and not satisfactory.

Fig. 8.1
figure 1

A precursor of the NHC ligand 15

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Suzuki–Miyaura couplings of primary alkyl halides with organoboron compounds were successful; whereas until recently, secondary and tertiary alkyl halides had been assumed to be improper substrates for the analogous cross-coupling reactions due to their difficulty of oxidative addition caused by the large steric hindrances [50, 51]. But, Fu has succeeded in Suzuki–Miyaura coupling of inert secondary alkyl iodides and bromides by using nickel (0) complexes with the bathophenanthroline ligand 16 (Eq. 8.25) [52]. Duncton et al. have applied this type of reaction to the cross-coupling reactions of oxetane iodides with azetidine; and they have synthesized the corresponding aromatic azetidines, which are known to be important motifs of the pharmaceuticals [53].

(8.25)

In 2006, Fu enabled the reactions of primary and secondary alkyl bromides (Eq. 8.26) and primary and secondary alkyl chlorides (Eq. 8.27), which were previously reported to be unreactive substrates. Fu catalyzed these reactions via nickel incorporated with the amino alcohol ligands 17 and 18 [54]. In these protocols, an advantageous feature is the use of the air-stable nickel (II) salts as precursors of the nickel catalysts—unlike the highly unstable Ni(cod)2.

(8.26)
(8.27)

In addition, Fu succeeded in 2007 in the room temperature Suzuki–Miyaura coupling reactions of primary alkyl iodides and bromides by combining the chiral 1, 2-diamine ligands 19 with the nickel (II) salts (Eq. 8.28) [55]. The mild reaction conditions of these reactions made possible the use of the alkyl boron compounds bearing various functional groups (esters, ethers, carbamic acids, etc.).

(8.28)

Reports have been compiled concerning the stereochemistry in the Suzuki–Miyaura coupling reactions of a series of alkyl halides. In 2007, Rodríguez et al. reported Suzuki–Miyaura coupling reactions of secondary 1-bromoethyl arylsulfoxides with various arylboronic acids using the palladium catalyst (Eq. 8.29) [56]. In this reaction, the conformational inversion of the stereogenic center occurred in a stereo-specific manner.

(8.29)

Later, Fu reported highly enantioselective Suzuki–Miyaura coupling reactions of secondary homobenzylic bromides with alkylboranes by using the chiral diamine ligands 20 (Eq. 8.30) [57]. This reaction is the first example of highly enantioselective Suzuki–Miyaura coupling reactions of the alkyl electrophiles.

(8.30)

Fu has reported the alkyl–alkyl Suzuki–Miyaura coupling reactions of the inert secondary alkyl chlorides—substrates that had been difficult to employ until very recently (Eq. 8.31) [58]. This reaction proceeded at room temperature, using the nickel (II) salts in the catalyst system with the chiral diamine ligands 21. This reaction can also be applicable to secondary alkyl bromides and primary alkyl chlorides.

(8.31)

Additionally, Fu succeeded in applying the above-mentioned reactions to enantioselection of the racemic secondary alkyl chlorides, activated by the amide functionalities, with arylboron compounds. The reactions catalyzed by the nickel complex incorporated with the ligand 22 took place under extremely mild reaction conditions at −5 °C and gave optically active alkylamides with up to 94 % (Eq. 8.32) [59].

(8.32)

Subsequently, Fu reported the enantioselective alkyl–alkyl-type Suzuki–Miyaura coupling reactions of inert secondary alkyl chlorides with alkylboron compounds (Eq. 8.33) [60]. In this reaction, the chiral coupled products were synthesized from the racemic acylated halohydrins and alkylboron compounds, yielding high enantioselectivity with the assistance of the nickel catalyst ligated with a chiral diamine ligand 23.

(8.33)

Very recently, Fu et al. reported the stereoconvergent alkyl–alkyl-type Suzuki–Miyaura coupling reactions of inert secondary alkyl chlorides substituted with amines (Eq. 8.34) [61]. Detailed mechanistic studies indicated that the primary site of coordination of the arylamine substrates to the nickel complex having the diamine ligand 24 was the nitrogen, not the aromatic ring. The kinetics for these asymmetric cross-coupling reactions of unactivated alkyl electrophiles was studied for the first time; the data were consistent with transmetalation being the turnover-limiting step of the catalytic cycle.

(8.34)

In contrast to their more commonly used nickel catalyst counterparts, the synthetic examples of Suzuki–Miyaura coupling reactions of secondary alkyl electrophile substrates promoted by palladium catalysts are comparatively rare. However, Falck et al. have recently reported the stereo-specific cross-coupling reactions of chiral secondary alkyl-substituted cyanohydrin triflates with the sp2 hybridized organoboron compounds in the presence of palladium catalyst 25 (Eq. 8.35) [62].

(8.35)

An example of Suzuki–Miyaura coupling reactions of secondary alkyl electrophiles using cheaper transition metals is the iron-catalyzed Suzuki–Miyaura coupling of inert alkyl halides with aromatic pinacolborates, achieved by Nakamura et al. (Eq. 8.36) [63]. Pertinent features of these reactions include the use of the iron catalyst 26 and a magnesium salt as a co-catalyst and the sterically bulky, bidentate phosphine ligands.

(8.36)

The regio- and stereo-selective synthesis of tetra-alkylated olefins has been very recently attained (Eq. 8.37) [64]. The R2 group was incorporated by Negishi coupling of 1-iodo-1-borylated olefins with primary alkyl bromides through zirconacyclopentene formation (derived from alkynylboronates and the low-valent zirconocene complex). Subsequent Suzuki–Miyaura coupling reactions of trialkyl-substituted alkenyl boronates afforded the tetra-substituted olefins having four different alkyl groups.

(8.37)

6 Hiyama Coupling

The synthetic examples of Hiyama coupling reactions of alkyl halides as the coupling partners are comparatively few, but have gradually increased in number in recent years. For instance, in 2003 Fu et al. reported Hiyama coupling reactions of inert primary alkyl halides with aryl silicon compounds, utilizing palladium with the PtBu2Me ligand (Eq. 8.38) [65]. This reaction is based on previously reported Suzuki–Miyaura coupling conditions [45, 48], and is promoted by further adding Bu4NF as an activator to generate highly nucleophilic, hyper-valent silicon-containing species. As a result, this reaction occurred at room temperature and showed high functional groups tolerance.

(8.38)

In addition, Fu achieved Hiyama coupling of inert secondary alkyl halides with aryltrifluorosilanes by using nickel having the ligand 27 as the catalyst (Eq. 8.39) [66]. This reaction can also be applicable not only to primary alkyl bromides and chlorides but also to the cyclic and non-cyclic secondary alkyl bromides, as well as the cyclic secondary alkyl iodides. It has also been clarified that these reaction conditions can be effective for the analogous Negishi and Suzuki–Miyaura couplings, employing the same types of the substrates.

(8.39)

In 2007, Fu reported Hiyama coupling reactions of secondary alkyl bromides and chlorides with the aromatic silicon compounds, with the aid of the nickel catalyst system, i.e., nickel (II) chloride with the norephedrine ligand 28 (Eq. 8.40) [67]. This reaction was modified with the use of new ligands, based on the previously reported Suzuki–Miyaura coupling conditions [54]. It became clear that this reaction was applicable to secondary alkyl bromides and iodides as well as the activated secondary alkyl chlorides, which had not been successfully used as the substrates prior to this work.

(8.40)

In 2008, Fu et al. reported the nickel-catalyzed asymmetric Hiyama coupling reactions of the racemic secondary α-bromoesters, employing diamine ligands 29 to give the corresponding chiral secondary esters with high enantioselectivity (Eq. 8.41) [68]. Anhydrated tetrabutylammonium triphenyldifluorosilicate (TBAT), as an activator, was the essential component to accelerate this reaction.

(8.41)

7 Sonogashira–Hagihara Coupling

In 2003, Fu reported Sonogashira–Hagihara cross-couplings of alkyl bromides and iodides by using a palladium catalyst ligated with N-heterocyclic carbene ligands 30 (Eq. 8.42) [69]. It was found that this reaction could be applicable to primary alkyl bromides and iodides even under mild conditions, but the alkyl chlorides were reported to be unsuitable.

(8.42)

In 2006, Glorius et al. reported the first Sonogashira–Hagihara coupling of secondary alkyl bromides using the palladium catalyst bearing the bioxazoline-derived N-heterocyclic carbene ligands 31 (Eq. 8.43) [70]. This reaction could be extended to the use of primary and secondary alkyl bromides, and the reactive functional groups such as esters and epoxides were compatible with these reactions.

(8.43)

Hu et al. reported in 2009 the nickel-catalyzed Sonogashira–Hagihara coupling reactions of inert alkyl halides by using the nickel complex 32 bearing the pincer-type ligands (Eq. 8.44) [71]. In these reactions, a series of alkyl chlorides, bromides, and iodides were used as the substrates. This is the first example for Sonogashira–Hagihara coupling of unactivated alkyl chlorides.

(8.44)

8 Summary

In this chapter, the recently reported examples of the cross-couplings of the alkyl electrophiles are collectively introduced. The cross-coupling reactions of the alkyl electrophiles have expanded the territory of the stereo-specific reactions toward the asymmetric syntheses. Because these reactions are tremendously useful for the synthesis of complicated organic molecules and the natural products bearing the alkyl chains as functional groups, further development of more efficient and selective reactions is highly anticipated. The further achievement of novel reactions by inexpensive and more active catalysts and the expansion to overcome the limitations of organometallic nucleophiles with reactive functional groups will be important future breakthroughs.