High-Valent NiIII and NiIV Species Relevant to C-C and C-Heteroatom Cross-Coupling Reactions: State of the Art.

Ni catalysis constitutes an active research arena with notable applications in diverse fields. By analogy with its parent element palladium, Ni catalysts provide an appealing entry to build molecular complexity via cross-coupling reactions. While Pd catalysts typically involve a M0/MII redox scenario, in the case of Ni congeners the mechanistic elucidation becomes more challenging due to their innate properties (like enhanced reactivity, propensity to undergo single electron transformations vs. 2e- redox sequences or weaker M-Ligand interaction). In recent years, mechanistic studies have demonstrated the participation of high-valent NiIII and NiIV species in a plethora of cross-coupling events, thus accessing novel synthetic schemes and unprecedented transformations. This comprehensive review collects the main contributions effected within this topic, and focuses on the key role of isolated and/or spectroscopically identified NiIII and NiIV complexes. Amongst other transformations, the resulting NiIII and NiIV compounds have efficiently accomplished: i) C-C and C-heteroatom bond formation; ii) C-H bond functionalization; and iii) N-N and C-N cyclizative couplings to forge heterocycles.

1. Introduction

Cross-coupling reactions mediated by organometallics represent a cornerstone in the daily synthetic Chemist’s toolbox leading to complex organic scaffolds [1,2]. Since the pioneering approaches to C–C coupling in the 1960s [3], the field has experimented tremendous advances with plenty of applications in material science, drug discovery and manufacturing, or natural product synthesis [1,2]. While n class="Chemical">Pd catalysts are commonly the candidates of choice, nickel is attracting growing attention owed to its higher abundance and economic issues [4,5,6]. On the other hand, and what is considerably more relevant, the enhanced reactivity and diversity in terms of redox properties of nickel (compared to palladium) offers broad room for reaction discovery [7,8]. Since the late 1970s, Ni catalysts have been employed with success in cross-coupling reactions [9,10], with the classical Ni0/NiII vs. NiI/NiIII pathways and single electron transfer (SET) processes being commonly proposed as the most plausible redox scenarios [11,12,13]. High-valent NiIII and NiIV key intermediates were recently invoked in C–C and C–heteroatom bond forming reactions, albeit their isolation or detection/characterization are typically out of reach [14,15,16,17,18,19]. First, spectroscopical identification of a NiIII mediating cross-coupling reactions was performed by Kochi and co-worker as early as 1978 [20]. In this seminal work, electron paramagnetic resonance spectroscopy (EPR) and UV-Vis spectroscopy allowed one to identify the trans-[(PEt3)2NiIII(2-MeOC6H4)(Br)]+ species that underwent C(sp2)–Br coupling. While additional NiIII and NiIV complexes were isolated and characterized in the following decades [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36], investigations dealing with the isolation and characterization of Ni species in high oxidation states (+3 and +4) that are efficient in cross-coupling reactions remained latent until this century. Built on the growing interest on high-valent species, this review compiles the most remarkable pieces of work addressing the long-time elusive NiIII and NiIV compounds (or analogous entities lacking Ni–C bonds) that are engaged in cross-coupling events or related transformations.

2. C–C Bond Forming Reactions Mediated by High-Valent NiIII and NiIV

Unlike Pt and n class="Chemical">Pd, the chemistry of organonickel species in the oxidation state +4 is underdeveloped. Nowadays, Pt-chemistry is mainly dominated by PtII and PtIV complexes and a plethora of stable R-PtIV species are known since the origins of organometallic chemistry. Routes to access aryl- and alkyl-PdIV complexes have appeared over the last 40 years displaying very distinct and complementary reactivity patterns to the ones observed for Pd-analogs in low oxidation states. It seems obvious that going up in the group makes the study of organometallic MIV derivatives more challenging. On the other hand, NiIV intermediates are often depicted in catalytic cycles [10,11,12,13,14]. Thus, the isolation, characterization and study of Ni species in oxidation states +3 and +4 represents a major challenge in modern organometallic chemistry.

Literature dealing with authenticated NiIII and n class="Chemical">NiIV samples and their use in cross coupling reactions was absent until the 2000s, when the pseudotetrahedral alkyl-NiIV species 2 was reported by Dimitrov and Linden (Scheme 1) [37]. The triorganyl-NiIV complex 2 was prepared through a 2e− oxidation step of the tris(1-norbornyl) precursor 1 with O2, and was fully characterized using nuclear magnetic resonance spectroscopy (NMR), X-ray diffraction (XRD), and elemental analysis (EA). The stability of 2 is probably given by the strong σ-donicity of the 1-norbornyl ligands. Remarkably, 2 resulted unstable at room temperature (r.t.) in solution and underwent elimination of dinorbornane (3). Alternatively, 3 was prepared upon addition of (1-norbornyl)lithium without the identification of the homoleptic tetraorganyl-NiIV intermediate.

Scheme 1

Isolation of the first NiIV complex 2 that proved active in C–C bond forming reactions. Adapted from reference [37].

The first homoleptic n class="Chemical">NiIV complex 5 was made via two oxidative couplings of 4 with [Ni0(COD)2] (COD = 1,5-cyclooctadiene) allowing to build the spirocyclic motif in 5 (Scheme 2) [38,39]. 5 was characterized using NMR and XRD, and proved stable upon heating or exposure to air. The enhanced stability of 5 was provided by the high shielded geometry around the NiIV-center imposed by the rigidity and bulkiness of the alkyl-based chelating ligands. Interestingly, 5 comes along with the trans,-trans,trans-cyclobutane 6 that was formed in 36% yield. In contrast, the remarkable stability of 5 pointed to the reductive elimination (R.E.) of 6 from a low-valent nickelacycle. Alternatively, 6 was eliminated in ca. 40% yield upon mild heating of the tris((5Z,11E)-dibenzo-[a,e]cyclooctatetraene)nickel(0) species 7, which was prepared from [Ni0(Bu3P)(COD)] and 4.

Scheme 2

Synthesis of the homoleptic NiIV spirocycle 5 and formation of cyclobutane 6. Adapted from reference [38].

A couple of papers detailing the isolation, characterization (XRD, 1H n class="Chemical">NMR, magnetic data, and EA), and reactivity of the T-shaped NiIII-CH3 complex 10 were reported by Tilley (Scheme 3) [40,41]. 10 was prepared through oxidative addition of MeI to a NiI species generated through reduction of the stable [NiII(N(DIPP)SiMe3)2] precursor 8 using KC8. 10 is conveniently stabilized by the two rigid and bulky bis(amido) ligands, but slowly decomposes to 8 with concomitant ethane production. In addition, 8 catalyzed the coupling of aryl halides and Grignard reagents.

Scheme 3

C–C coupling active NiIII-CH3 species 10 isolated and characterized by Tilley. Adapted from references [40,41].

Mirica has isolated the high-valent aryl-NiIII compounds n class="Chemical">14-Cl and 14-Br that underwent C–C coupling with alkyl Grignard reagents (Scheme 4) [42]. 14-Cl and 14-Br are stabilized by the N,N-di-tert-butyl-2,11-diaza[3.3](2,6)pyridinophane () ligand and were achieved in a two-step fashion through: i) an initial coordination of the ligand to Ni0, followed by insertion into the C–X bond and ii) 1e− oxidation using ferrocenium hexafluorophosphate [Fc+][PF6]. XRD, EPR, paramagnetic NMR, and magnetic data for 14-Cl and 14-Br confirmed the octahedral coordination of Ni and pointed to the presence of a mostly NiIII located unpaired electron. 14-Cl and 14-Br reacted with MeMgI at −50 °C to afford 15. Notably, 15 constitutes the first di(hydrocarbyl)-NiIII intermediate (identified using ESI-MS and EPR), and underwent the R.E. of 4-fluorotoluene (13) in moderate yield (48%). An improved yield (63%) was reached in a one-pot reaction of the aryl-NiII-Br complex 11-Br with MeMgBr and [Fc+][PF6]. The addition of 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) as a radical trap did not affect the coupling reaction and ruled out the involvement of organic radicals. In addition, the NiII and NiIII complexes 11-Cl, 11-Br, 14-Cl, and 14-Br proved suitable in Negishi and Kumada couplings.

Scheme 4

Proof of concept for the participation of aryl-NiIII complexes 14-Cl, 14-Br, and 15 in C–C bond forming reactions with alkyl Grignard reagents. Adapted from reference [42].

The lack of selective methods for aromatic trifluoromethylation represents a major concern [43,44,45]. This is mainly due to: i) the steadily increasing demand of organofluorine materials in pharmaceutical, agrochemical, and medical applications, or in material science [46,47,48] and ii) the disfavored transition n class="Chemical">metal mediated aryl–CF3 bond formation due to the strong M–CF3 bonds. It is believed that the current lack of environmentally-benign [49,50,51] and industrially-suitable routes to benzotrifluorides impedes faster advance in drug discovery. The impossibility to achieve aryl–CF3 R.E. from a well-defined, low-valent aryl-NiII-CF3 fragment was soon noticed independently by the groups of Vicic [52] and Grushin [53]. An elegant and certainly underexplored approach to enable the decisive R.E. step consists in the preparation of highly reactive NiIII and NiIV complexes, which are commonly inaccessible. Taken all together, the use of CF3-groups in organometallic chemistry offers a unique balance between stability and reactivity that allows for the isolation of high-valent compounds with strong M–CF3 bonds, yet enables CF3-group transfer into strategically designed organic scaffolds. While high-valent Ni species were unidentified, Ph–CF3 bond formation was achieved by Sanford’s team upon 1e− oxidation of well-defined [(P2)NiII(Ph)(CF3)] platforms using the outer-sphere oxidant [Fc+][PF6] [54]. These studies have shown the crucial role of the ancillary diphosphine ligand on the R.E. of benzotrifluorides [54]. As might be expected, small bite angles (β < 92°) conducted to insignificant amounts of benzotrifluoride (<10% yield), whereas bite angles ranging from 95° to 102° favored the aryl–CF3 coupling (up to 77% yield).

The first approach to high-valent Nin class="Chemical">CF3 species was reported by Vicic and co-workers [55]. They prepared and characterized in situ the cationic [(terpy)NiIII(CF3)2][PF6] species 16 using low-temperature EPR (Scheme 5). Unfortunately, 16 turned out to be unstable at r.t. and yielded complex [(terpy)NiII(CF3)]+ via ●CF3 radical elimination. The use of a perfluorinated nickelacycle motif in 17 warranted the NiIII stabilization and permitted its characterization using XRD and EPR [56]. Cyclic voltammetry of 17 displayed a low redox potential attributable to the reversible NiII/NiIII couple, whereas elevated redox potentials are required to overcome the NiIII/NiIV oxidation potentials. The first isolable NiIII-CF3 compounds and were obtained in reasonable yields by Mirica’s group using highly donating tetradentate pyridinophane ligands and [57]. and were characterized using XRD, EPR, and computed by DFT (density functional theory). Besides the trifluoromethylation of the radical scavenger PBN (phenyl N-t-butylnitrone), no evidence was provided for the participation of 16- in trifluoromethylation reactions. Instead, a ligand modification strategy was highlighted to be key in order to lower the redox potential of the NiIII/NiIV couple [56].

Scheme 5

Stable NiIII-CF3 complexes 16, and and perfluorinated nickelacycle 17 [55,56,57].

In spite of the significant number of NiIV coordination compounds that have been known since ca. 40 years ago [27,28,29,30,31,32,33,34,35,36], whn class="Chemical">ether NiIV species are engaged in cross-coupling reactions or not has remained unclear until very recently. In 2015, Camasso and Sanford made a cutting-edge discovery: the isolation and complete characterization of the first NiIV compounds able to promote cross-coupling events [58,59,60]. Based on previous knowledge on related PdIV-chemistry [61,62,63,64,65,66,67,68], an isolable NiIV platform was designed through the combination of three distinct strategies: i) the use of strongly N-donor, tridentate scorpionate-type ligands [i.e., tris(pyrazolyl)borate (Tp) and tris(2-pyridil)methane (Py3CH)]; ii) the presence of the Ni(cyclo-neophyl) core known to improve stability vs. R.E. and H-elimination elementary steps; and iii) the employment of a σ-donating CF3-ligand (Scheme 6) [58]. Following these premises, the Umemoto reagent S-(trifluoromethyl)dibenzothiophenium triflate (TTDT) was added to 19, and the diamagnetic NiIV complex 20 was obtained in 92% yield. The high stability of nickelacycle 20 allowed its full characterization, including XRD that confirmed the facial coordination of the Py3CH ligand to the octahedral NiIV-center. Heated to 95 °C, 20 underwent C(sp2)–C(sp3) reductive elimination to afford quantitatively the 1,1-dimethylbenzocyclobutene 21. This work represents the first spectroscopic support for the participation of NiIV species in cross-coupling reactions.

Scheme 6

Synthesis of the NiIV complex 20, and its use in C–C bond formation via reductive elimination (R.E.). Adapted from reference [58].

In a following report, they performed the trifluoromethylation of aromatics from a well-defined aryl-n class="Chemical">NiIV-CF3 fragment [69]. On this occasion, the high-valent NiIV-CF3 complexes 24a–e were stabilized by the tris(pyrazolyl)borate (Tp) ligand and two CF3-groups. 24a–e were obtained through a 2e− oxidation step of the NiII-CF3 precursor 22 with aryliodonium salts at −35 °C in acetonitrile (Scheme 7; top left) [69]. Alternatively, the NiII to NiIV conversion can be reached using the Umemoto reagent (TTDT) as demonstrated by the high-yielding isolation of 24a from [(Tp)NiII(Ph)(CF3)] (25a; bottom left in Scheme 7) [69]. Once isolated and fully characterized, complexes 24a–e were heated to 55 °C undergoing the elimination of the corresponding benzotrifluorides 26a–e accompanied by [NiII(Tp)2] and [NiII(CH3CN)2(CF3)2].

Scheme 7

Distinct oxidation strategies to reach the NiIV species [NiIV(Tp)(aryl)(CF3)2] 24a–e from [NMe4][NiII(Tp)(CF3)2] (22) and aryliodonium salts (top left) or [NBu4][NiII(Tp)(Ph)(CF3)] (25a) and TTDT (bottom left), and R.E. of benzotrifluorides 26a–e from 24a–e. Adapted from reference [69].

Kinetic studies and Hammett plot analysis for the R.E. step enabling benzotrifluoride formation provided a ρ value of −0.91 indicating faster reaction rates with electron-enriched n class="Chemical">arenes [69]. This beneficial effect was attributed to the larger trans-effect of electron rich arenes, along with the lower kinetic barriers associated with the nucleophilic attack of the electron rich σ-aryl ligand to the electrophilic CF3-group [69]. However, the bonding analysis of complex 24a pointed to an inverted ligand field situation [70] and the NiIV complexes 24a–e are better described as NiII species. This effect was called the σ-noninnocence of the cationic aryl ring [70] and the release of PhCF3 through a redox neutral R.E. step via “σ-noninnocence-induced masked aryl-cation transfer”, accordingly [70].

The use of Py3CH or n class="Chemical">Tp ligands is necessary for accessing the NiIV species 20 and 24a–e as shown by the reduced stability of analogous platforms bearing less donating bipyridine ligands (bpy or dtbpy; Scheme 8) [58,69]. As a result, the presumable NiIV-CF3 intermediates 28 and 31a were exclusively identified using low-temperature NMR analysis, and rapidly released 1,1-dimethylbenzocyclobutene 21 or benzotrifluoride 26a at r.t., respectively. Replacement of the CF3-group by a distinct X-type ligand (i.e., halides, tosylate, or acetate) reduced the stability of NiIV, thus favoring the C(sp2)–C(sp3) R.E. and hampering the detection of NiIV species.

Scheme 8

Identification of the NiIV-CF3 key intermediates 28 and 31a bearing bpy (a) or dtbpy (b) ligands, and subsequent R.E. steps upon warming up to r.t. Adapted from references [58,69].

Shortly after, they evaluated the capacity of similar NiIII complexes 33a–d to forge diverse C–C bonds (Scheme 9) [71]. The n class="Chemical">NiIII 33a–d were achieved in variable yields from 22 and 32a,c,d through a 1e− oxidation process with AgBF4. The isolated NiIII materials were characterized using EPR and XRD. Heated in acetonitrile, 33a,c,d decomposed into [NiII(Tp)2] and Ni0 with concomitant formation of the C–C coupled products in 33–69% yield. Remarkably, 33b merely produced 1% of hexafluoroethane. For complex 33a displaying the Ph-NiIII-CF3 fragment, enhanced rate and yield of benzotrifluoride 26a was reached in the presence of oxidants, such as [(Cp*)2Fe][BF4]. This observation was attributed to the efficient quenching of the resulting NiI species generated in situ during Ph–CF3 formation. Detailed mechanistic investigations have demonstrated the direct R.E. from the NiIII species 33a,c,d (instead of the assumed NiIV derivatives).

Scheme 9

Syntheses of NiIII species 33a–d (a), and R.E. studies enabling Ph–CF3 coupling (b). Adapted from reference [71].

More recently, Mirica’s group has reported the synthesis and complete characterization of the high-valent NiIII and n class="Chemical">NiIV compounds 36 and 37 enabled by: i) facial coordination of the tridentate ligand 1,4,7-trimethyl-1,4,7-triazacyclononane (Me3tacn) and ii) the Ni(cyclo-neophyl) skeleton (Scheme 10) [72]. Complexes 36 and 37 were prepared in high yield from the NiII-precursor 35 through two successive 1e− oxidation steps with ferrocenium tetrafluoroborate ([Fc+][BF4]) and acetylferrocenium tetrafluoroborate ([AcFc+][BF4]). XRD studies confirmed the atom connectivity in 36 and 37 along with their square pyramidal and octahedral geometry, respectively. Heated to 80 °C, the NiIV complex 37 underwent C(sp2)–C(sp3) R.E. in modest yield while blue LED irradiation drove to almost quantitative formation of 1,1-dimethylbenzocyclobutene 21. Interestingly, exposure of the NiIII species 36 to blue LED did not improve the reaction yield. This work argues in favor of NiIV being most likely the coupling active species when dealing with dual Ni/photocatalytic approaches (instead of the commonly invoked NiIII intermediates) [73,74,75,76].

Scheme 10

NiII/NiIII/NiIV oxidation process starting from the Ni(cyclo-neophyl) 35 and R.E. studies from high-valent species 37 upon heating or blue LED irradiation. Adapted from reference [72].

The tetradentate N,N-dimethyl-2,11-diaza[3.3](2,6)pyridinophane ligand () enabled the isolation and full characterization of the first n class="Chemical">NiIII-dialkyl complex 41. It was achieved from the square planar NiII precursor 38 and [Fc+][PF6] (Scheme 11a) [77], and its octahedral geometry was confirmed using XRD and EPR. 41 in acetonitrile produced ethane and methane in ca. 55% and 30%, respectively. Ethane production was improved upon addition of [AcFc+][PF6] pointing to the formation of an elusive NiIV-dialkyl intermediate 42 that decomposes rapidly to NiII material and ethane via a R.E. step. In order to stabilize the high-valent species, the cyclo-neophyl group was incorporated to the NiII platform (Scheme 11b) [77]. The two-step oxidation of 45 with [Fc+][PF6] to give the NiIII intermediate 46, followed by addition of NOPF6 permitted the identification of the NiIV compound 47, which was characterized using NMR and X-ray photoelectron spectrometry (XPS). The enhanced stability of the NiIII and NiIV compounds 46 and 47 (vs. 43 and 44) inhibited the R.E. and led to 21 in low yields (10% and 38%, respectively).

Scheme 11

Syntheses of NiIII and NiIV dialkyl complexes 41–44 and R.E. of ethane (a). Syntheses of stable NiIII and NiIV cyclo-neophyl complexes 46 and 47 (b). Adapted from references [77,78].

In a subsequent article, the same group reported the synthesis and characterization of analogous NiIII-dialkyl complexes 43 and 44 incorporating n class="Chemical">NMe/NTs or NTs/NTs donating groups [78]. The low donicity of the TsN-amino groups favored the formation of transient penta- or tetra-coordinated NiIII-dialkyl species that are more prone to eliminate ethane (Scheme 11a) [78]. Compounds 43 and 44 are easily accessible in presence of O2 or H2O2 and underwent selective C–C bond formation. In addition, the quantitative formation of 21 was accomplished from an elusive NiIV-complex 48, very similar to 47 but with TsN-amino groups [79].

As shown earlier, NiIII and n class="Chemical">NiIV complexes are engaged in C–C bond forming reactions, although limited knowledge is available concerning their comparative efficiency upon similar environments such as identical geometry, type of ligands or ligand set, and global charge. In this sense, Sanford’s group has evaluated the feasibility of C–C and C–heteroatom bond formation depending on: i) the nature of the transition metal (Ni vs. Pd) [80]; ii) the nature of the surrounding ligands (MeCN vs. CF3) [80]; and iii) the oxidation state at Ni (+3 vs. +4; see Scheme 12) [81].

Scheme 12

C–C bond formation as a function of the metal (Ni vs. Pd; a), ancillary ligand (Tp vs. Py3CH and CF3 vs. MeCN; b and a, respectively) or oxidation state at the Ni-center (+3 vs. +4; a). Adapted from references [80,81].

Organometallic compounds 50–52 bearing a n class="Chemical">tris(pyrazolyl)borate ligand (Tp) were prepared from the corresponding salts [Q+][(Tp)MII(cyclo-neophyl)] (Q+ = K+, NMe4+; M = Ni, Pd) through selective 1e− or 2e− oxidation processes. Kinetic studies performed for the elimination of 21 from the MIV species 50, 51, and 52 proved the higher stability of 50 vs. 52, most likely due to the strong σ-donation of the CF3-group. The nature of the cationic species (Tp)-NiIV 52 and (Py3CH)-NiIII 53 was authenticated using XRD, EPR (53) or NMR (52), and cyclic voltammetry [80,81]. Their ability to release 21 was then compared at r.t. in the dark or when exposed to daylight (Scheme 12), thus reflecting the higher activity of the (Py3CH)-NiIII complex 53. It provided the coupled product in 87% yield after 12 h in the dark, whereas the NiIV released negligible amounts of 21 (<10%; 300-fold slower than 53). Exposure to daylight improved the efficiency of the NiIV complex 52 to form the C–C bond (65% in 12 h), while no remarkable effect was accounted for the NiIII 53.

In 2017, the group of Sanford reported the transmetallation reaction between the n class="Chemical">NiIV-O2CCF3 complex 54 and Ruppert’s silane in presence of [Me4N][F] leading to NiIV-CF3 complex 55 (Scheme 13; the synthesis, characterization and reactivity of 54 is depicted below in Scheme 30) [82]. The NiIV-CF3 compound 55 was conveniently characterized using NMR methods and XRD and underwent aromatic trifluoromethylation leading to 56 in ca. 90% yield upon warming at 70 °C overnight. The addition of the electron rich PMe3 ligand improved kinetics and yield of aryl–CF3 production.

Scheme 13

Transmetallation reaction between the NiIV-O2CCF3 complex 54 and CF3TMS/NMe4F to reach 55, and synthesis of the NiII species 56 via R.E. of aryl–CF3. Adapted from reference [82].

The same year, Ribas and co-workers reported the quantitative trifluoromethylation of triaza-macrocycles bearing an aromatic ring [83]. The reaction involves two independent steps namely: i) an n class="Chemical">aryl-NiII bond formation to reach 57a,b via aryl–Br oxidative addition to [Ni0(COD)2], or alternatively, C–H bond nickelation using [NiII(NO3)2]•6(H2O); and ii) the oxidative trifluoromethylation of the macrocyclic scaffold upon addition of the Umemoto or Togni reagents (Scheme 14) [83]. The authors proposed a NiII to NiIV oxidation step prior to R.E. of the coupled products 58a,b through an initial SET process to form a (N3Carom)NiIII intermediate and a ●CF3 radical that subsequently recombine with each other to build the (N3Carom)NiIV species 59a,b.

Scheme 14

Oxidative trifluoromethylation of N3Carom ligands mediated by Ni. C–CF3 bond formation from the elusive (N3Carom)NiIV intermediates 59a,b. Adapted from reference [83].

Klein, van der Vlugt and co-workers performed the 1e− oxidation of the n class="Chemical">NiII-CH3 complex 60 upon addition of [AcFc+][BF4] to yield the transient NiIII-CH3 species 61 bearing an aryl-pyridine-phosphine (PNCarom) pincer ligand (Scheme 15) [84]. Reaction monitoring using 1H NMR indicated the formation of the tolyl fragment and the release of the NiI complex 62, which was identified using EPR.

Scheme 15

Aryl–CH3 coupling from an assumed cationic [(PNCarom)NiIII(CH3)]+ pincer complex 61. Adapted from reference [84].

A ligand design strategy allowed the development of the oxidative cyanation of aromatic rings enabled by a NiIII-Cn class="Chemical">N key intermediate 65 (Scheme 16) [85]. Insertion of [Ni0(COD)2] into the triaza-macrocycle provides [(BuN3C)NiII(Br)] (63). 63 further reacts with TlPF6 and BuNC affording the highly stable bis(isocyanide) compound [(BuN3C)NiII(BuNC)2][PF6] (64). In contrast, oxidative treatment of 64 with [Fc+][PF6] or NOBF4 yielded the cyanide-containing macrocycle instantaneously. The NiIII-mediated N–Bu heterolytic bond scission to give the NiIII-CN species and isobutylene was proposed in line with: i) the high stability of the NiII-CNBu species 64; and ii) the quantitative yield of attained upon addition of AgCN to [(BuN3C)NiII(Br)] (63) [86]. The bis(acetonitrile) NiIII complex (66) was conveniently characterized using XRD and EPR, and was reacted with BuNC resulting in the liberation of . Monitoring the coupling reaction illustrated the simultaneous consumption of 66 and the formation of , thus suggesting the participation of NiIII species in the N–Bu bond breaking/aryl–CN bond forming sequence.

Scheme 16

NiIII-mediated aromatic cyanation using BuN-containing pyridinophane scaffolds. Adapted from reference [85].

The nature of the pending RN-amino groups located at the apical positions drastically affects the stability and reactivity of the n class="Chemical">NiIII species, whereas modification of the aryl moiety does not impact reactivity significantly [87]. Complex 67 undergoes the full cyanation of the aromatic ring upon addition of BuNC in air (Scheme 17) [87]. Alternatively, can be forged through initial bromide abstraction and exposure to air. These aerobic cyanations occur at r.t. within 5 min and imply the transient formation of NiIII intermediates, as convincingly proved through the reactivity of the isolated NiIII 68 towards BuNC that afforded in quantitative yield. High-yielding syntheses of NiIII species 69 and 68 were accomplished via 1e− oxidation either with [Fc+][PF6] or AgBF4 [88]. A distorted octahedral coordination of Ni and the presence of an unpaired electron in 68 and 69 was confirmed using XRD, EPR, and magnetic measurements [88].

Scheme 17

NiIII-mediated aromatic cyanation using N-containing pyridinophane scaffolds. Adapted from references [87,88].

The viability of NiII/n class="Chemical">NiIII/NiIV oxidation sequences involving successive SET processes has been investigated recently (Scheme 18) [89]. The isolation and characterization of NiIV metallacycles 74a,b was accomplished by controlled release of alkyl and aryl radicals upon heating of the NiIII precursor 72 in presence of the corresponding diacyl peroxide 73a,b (Scheme 18a) [89]. An appropriate choice of perfluorinated ligand is necessary in order to enhance the NiIV stability, and negligible amount of NiIV-CF3 material was formed when starting from the parent compound 33b. In-depth mechanistic studies proved the release of free ●R radicals and their subsequent recombination with 72 to build the NiIV. In contrast, 74a can be synthesized in high yield from 72 and aryl radicals (aryldiazonium salts combined with ferrocene; Scheme 18a) [89].

Scheme 18

NiIII to NiIV oxidation mediated by carbon-centered radicals (a), and C–C coupling from NiIV-CH3 75 and diacyl peroxides 73a–c. Adapted from reference [89].

On the other hand, the diamagnetic NiIV-CH3 species 75 was prepared in moderate yield from the n class="Chemical">NiII-CF3 complex 22 and MeI, and was characterized using multinuclear NMR and EA. Most remarkably, 75 reacted with carbon-based ●R radicals (generated from diacyl peroxides 73a–c) and underwent R–CH3 bond formation (65–78% yield; Scheme 18b) [89]. The operative radical substitution (S) pathway and the absence of free ●CH3 radicals were concluded according to: i) the observed product distribution; ii) the lack of ethane formation; and iii) the marginal influence of β-nitrostyrene.

Thorough mechanistic studies including one- and two-dimensional 1H NMR experiments, deuterium labelling, kinetic and crossover experiments, and EPR monitoring was performed by Diao and co-workers to prove the involvement of the [(py-pyrr)NiIII(I)(CH3)]2 species 79 in C(sp3)–C(sp3) bond formation (Scheme 19) [90]. The mixture of high-valent isomers 79 was achieved upon 1e− oxidation of the NiII-precursor 77 with I2 at low temperature. The I-bridged binuclear complex 79 is diamagnetic due to antiferromagnetic coupling between the two low-spin NiIII centers. 79 was characterized using 1H and 13C NMR at low temperature and its structure was attributed according to DFT calculations and experimental observations. The capacity of 79 to mediate C(sp3)–C(sp3) couplings was demonstrated by simultaneous ethane formation and consumption of the NiIII-CH3 79 (Scheme 19) [90]. The bimolecular pathway was evidenced by crossover experiments, the observed dependence of the [CH3–CH3]/[CH3–I] ratio on [77], and the first order dependence in [79]. The synthesis of the NiIII-CH3 isomers in 79 and subsequent ethane formation involves: i) 1e− oxidation from NiII-CH3 77 to the square pyramidal NiIII-CH3 monomer 78 (EPR-identified); ii) dimerization of 78 leading to diamagnetic NiIII material 79 upon lutidine dissociation; and iii) C–C bond formation with concomitant reduction of 79 to NiII.

Scheme 19

Bimolecular C–C coupling enabled by the NiIII species 79. Adapted from reference [90].

3. C–Heteroatom Bond Formation Mediated by High-Valent NiIII and NiIV

Amongst all types of cross-coupling reactions, C–heteroatom bond forming reactions constitute a useful and reliable tool in organic synthesis leading to relevant heterocyclic scaffolds and aryl derivatives such as n class="Chemical">phenols or anilines. In marked contrast to Pd-catalyzed cross-coupling reactions that operate through a M0/MII catalytic loop, NiIII species are commonly accepted as key intermediates in C–heteroatom couplings since the early discoveries made by Kochi and co-worker in 1978 [20]. In this sense, seminal work by the group of Hillhouse has provided additional insights for the participation of cyclometallated NiIII compounds in the challenging C–heteroatom bond formation step that typically hampers catalytic turnover. Even though the authors failed to characterize the high-valent NiIII-intermediates, they have illustrated the potential utility of high-valent NiIII species in C–heteroatom couplings giving rise to pyrrolidine [91,92], 3,4-dihydrocoumarin [92,93], or aziridine [94] scaffolds.

The reactivity of the aryl-NiIII-X complexes n class="Chemical">14-Cl and 14-Br towards alkyl Grignard and alkyl Zn derivatives was reported in 2014 (Scheme 4) [42]. In absence of an alkyl-type organometallic partner, the high-valent species 14-Cl and 14-Br underwent C(sp2)–Cl and C(sp2)–Br bond forming reactions upon warming up to r.t. (Scheme 20) [42]. Alternatively, the addition of [Fc+][PF6] to the aryl-NiII complexes 11-Cl and 11-Br in acetonitrile at −50 °C and ensuing exposure to r.t. leads to the corresponding aryl halides in up to 72% yield. The stirring of NiIII complexes 14-Br and 81 in equimolar amounts at r.t. yielded the C(sp2)–X coupled products 80, 82–84 due to NiIII-X bond dissociation and subsequent C–halide bond formation. This work has provided the first spectroscopic evidence for the NiIV-involvement in C–heteroatom coupling.

Scheme 20

Proof of concept for the participation of well-defined aryl-NiIII-X intermediates 14-Br and 81 in C(sp2)–X bond forming reactions. Adapted from reference [42].

The addition of bromine (n class="Chemical">Br2) or its safer substitute [BnNMe3][Br3] to 85 led to the nearly quantitative isolation of the NiIVBr3 compound 86 bearing a bis-carbene pincer platform (DIPPCCC; Scheme 21) [95]. XRD and 1H NMR confirmed the atom connectivity and the octahedral coordination in 86. The 2e− reduction process in presence of organic substrates such as olefins or (mesityl)MgBr restores the NiII-Br 85 and yields the brominated products (Scheme 21).

Scheme 21

C–Br couplings enabled by NiIVBr3 species 86. Adapted from reference [95].

In analogy to PdIII-chemistry [96,97,98], the role of intermetallic interactions when dealing with cross-coupling reactions and high-valent Ni homobimetallics has been investigated (Scheme 22) [99]. Thus, the unprecedented Ni platforms 89 and 92 containing the benzo[h]quinoline ligands were isolated and characterized. XRD, EPR, and DFT analyses on the homobimetallic complex 89 pointed to: i) the presence of a binuclear Ni complex with a Ni–Ni bond order of ½; ii) an average oxidation state of +2.5 for each Ni-center; and iii) the stabilization of the electrodeficient [Ni2]5+ core by apical coordination of THF ligands. Addition of TDTT or PhICl2 to 89 afforded the coupled products in 90% and 75% yield, respectively. In contrast, the addition of bromide anions to 89 resulted unfruitful. The 2e− oxidation of the binuclear NiII complex 91 with [PhNMe3][Br3] gave rise to the NiIII–Br–NiIII species 92, which was characterized using XRD thereby proving the lack of a Ni–Ni bond. Warming up to r.t., the binuclear NiIII–Br–NiIII complex 92 underwent C(sp2)–Br bond formation and yielded 90-Br (Scheme 22) [99]. The high activity of the assumed NiIII–X–NiIII species coupled to the inactivity of the mixed-valence complex 89 seems to indicate that the C(sp2)–X coupling occurs at each NiIII-center only in absence of any Ni–Ni interaction.

Scheme 22

C(sp2)–X couplings enabled by high-valent NiIII–X–NiIII homobimetallic complexes. Adapted from reference [99].

The selective incorporation of fluorine atoms to organic scaffolds is highly desirable due to: i) the unfavored R–F coupling from a well-defined R–M–F fragment; and ii) the importance of n class="Chemical">organofluorine chemistry in industry [44,46,47,48]. An impressive strategy to build C(sp2)–18F bonds mediated by aryl-NiII precursors 93a–u, the iodine(III)-based oxidant 94 and aqueous 18F− has been recently developed by Ritter and colleagues (Scheme 23) [100,101].

Scheme 23

C(sp2)–18F coupling enabled by the NiII-platform 93a-u, aqueous 18F− and 94. Adapted from references [100,101].

A common hallmark in the NiII-platform 93a–u resides in the n class="Chemical">sulfonamide moiety included in the bidentate ancillary ligand, a mandatory requirement for the C(sp2)–18F bond forming reaction to proceed. While no high-valent Ni-species were initially detected, in situ EPR characterization of the key aryl-NiIII species 96s,t-MeCN, and 96s,t-F was carried out in a subsequent article (Scheme 24) [102]. Enhanced stability of NiIII was achieved upon the use of the more rigid NiII platforms 93s,t bearing the chelating σ-aryl-pyridine ligands. This strategy proved right, and the sulfonamide-stabilized key intermediates 96s-MeCN and 96s-F underwent C(sp2)–18F coupling upon mild heating. In sharp contrast, the constrained geometry displayed by the parent aryl-NiIII complexes 96t-MeCN and 96t-F prevented the aromatic fluorination.

Scheme 24

Aromatic fluorination enabled by NiIII–F intermediates. Adapted from reference [102].

A NiIV–F compound which enables aromatic fluorination has been recently reported (Scheme 25) [103]. The n class="Chemical">NiII complex 97 bearing the potentially tridentate tris(pyrazolyl)borate ligand (Tp) was reacted with selectfluor to afford the diamagnetic aryl-NiIV–F species 98 in ca. 50% yield. The NiIV nature of 98 was authenticated using NMR and XRD. Upon mild heating, 98 yielded 100 that further reacts with N2H4 to cleave the Ni–aryl bond producing the fluorobiphenyl 99. An analogous NiIV–F stabilized by 2,2′-bipyridine (bpy) ligand was identified using 19F NMR as well before quantitative C(sp2)–F bond formation. DFT-calculations supported a concerted C(sp2)–F reductive elimination pathway with lower activation barriers for the [(bpy)NiIV(aryl)(F)]+ key intermediate.

Scheme 25

Aromatic fluorination enabled by the NiIV–F complex 98. Adapted from reference [103].

After the discovery of C(sp2)–X coupling (X = n class="Chemical">Br or Cl) mediated by isolated NiIII complexes the participation of NiIII species in C(sp2)–O bond formation was studied (Scheme 26) [104]. The salts 101 and 66 were synthesized and fully characterized using XRD, EPR, and magnetic data. The NiIII–OR intermediates 103 and 104 were obtained by adding metallic alkoxides or hydroxides to 66 in alcoholic or aqueous media, respectively. Attempts to isolate 103 and 104 resulted unfruitful due to their high instability. Nevertheless, the structure of 103 was corroborated by: i) low-resolution XRD that confirmed its octahedral geometry; and ii) the large gave value of 2.192 obtained by EPR (vs. 2.145 and 2.125 for 101 and 66, respectively) that substantiated the coordination of the stronger σ- and π-donating methoxide ligands.

Scheme 26

NiIII-OR complexes 103 and 104, and their decomposition to build C(sp2)–OR bonds. Adapted from reference [104].

The NiIII-OMe 103 decomposes in n class="Chemical">THF at r.t. to and in ca. 1:1 ratio (Scheme 26) [104]. The addition of an exogenous oxidant (PhI(PyOMe)2OTf2) and additional KOMe improved the selectivity towards BuN3C–OMe bond formation. The parent NiIII-OH compound 106 displays a similar EPR pattern to 103 and decomposes rapidly to afford (32%) and (51%). The aryl–OR coupling takes place via a disproportionation reaction of 103 and 104 to generate an elusive [(BuN3C)NiIV(OR)3] species and subsequent R.E step.

Using the fully characterized NiIIIBr2 complex 105 (Scheme 27) [105,106], Cipso–heteroatom bond formation with several nucleophiles (n class="Chemical">water, methanol, ammonia, or hydrobromic acid) has been studied [107]. Metal–Ligand cooperation was invoked to cleave the H–Nu bond. Thus, a Me2N-sidearm decoordinates and attacks the proton to create the aryl-NiIII-Nu moiety that is required to make possible the C(sp2)–Nu coupling. Nevertheless, the coupled products are reached at best in ca. 50%. The structures of NiIII derivatives 109 and 108, prepared through halogen abstraction with AgSbF6, were elucidated using XRD and EPR (Scheme 27) [108]. Both NiIII species 108 and 109 underwent C(sp2)–O and C(sp2)–N couplings at r.t. with concomitant formation of 110. The low yields were attributed in part to unwanted side-reactions namely: i) the generation of NiII species 107 and 110; ii) protodemetallation; or iii) C(sp2)–OH coupling with adventitious water.

Scheme 27

NiIII-mediated C–O and C–N bond formation assisted by an NCaromN-pincer ligand. Adapted from references [107,108].

As mentioned before, the NiIV-n class="Chemical">CF3 compounds 20 and 50 bearing tridentate scorpionate-type ligands (Py3CH or Tp) underwent C(sp3)–C(sp2) cyclization (Scheme 6 and Scheme 12, respectively) [58]. Addition of heteroatom-based nucleophiles (i.e., alkoxides or amides) afforded the C(sp3)–heteroatom coupled complexes 111a–d (78–94% yield; Scheme 28) [58,80]. Swain–Scott nucleophilicity parameters and kinetic studies pointed to a SN2-type mechanistic pathway proceeding through nucleophilic attack of the exogenous heteroatom-based nucleophile into the NiIV–C(sp3) bond. Comparative kinetic studies with analogous (Tp)PdIVCF3 complexes proved the higher propensity of the NiIV-platform towards C(sp3)–OAc coupling [80]. Intriguingly, the addition of [NBu4][N3] to 50 produced 3,3′-dimethylindoline (114) via double C–N bond forming reaction [58,80]. The formation of 114 occurs as follow: i) first C(sp3)–N coupling giving rise to the diamagnetic NiII-CF3 complex 111e; followed by ii) N2-elimination and indoline-ring formation leading to the NiII-CF3 113e; and iii) protodemetallation step with adventitious water.

Scheme 28

Proof of concept for the involvement of NiIV in C–heteroatom bond formation via R.E. Adapted from references [58,80].

The reactivity of closely related high-valent species 52 and 53 towards tetramethylammonium acetate was recently addressed as well (Scheme 29) [80,81]. As depicted in Scheme 12, the n class="Species">C(sp3)–C(sp2) cyclization to yield 21 proceeds more easily from the NiIII 53 in dark conditions or exposed to daylight. Accordingly, addition of acetate as an exogenous nucleophile preferentially led to 21 in ca. 40% yield. In sharp contrast, the NiIV complex 52 underwent selective C(sp3)–OAc bond formation. Protonolysis with trifluoroacetic acid (TFA) delivered 116a. The very distinct reactivity of 52 vs. 53 was attributed to the significantly enhanced electrophilicity of the Ni–C(sp3) bond in the NiIV platform 52 vs. 53, thus favoring the nucleophilic attack via outer-sphere SN2 pathway.

Scheme 29

Reactivity of cationic NiIII and NiIV platforms 52 and 53 vs. [NBu4][OAc]. Adapted from references [80,81].

The NiIV–n class="Chemical">O2CCF3 species 54 was synthesized through 2e− oxidation of the anionic NiII complex 117 using bis(trifluoroacetoxy)iodobenzene (PhI(OTFA)2; Scheme 30) [82]. 54 was fully characterized (NMR, XRD, and EA) and proved stable in solution at −35 °C. In contrast, it slowly underwent C(sp2)–O bond formation in 2,5-dimethyltetrahydrofuran at r.t. Warming 54 up to 70 °C for 6 h led to heterocycle 119 through initial C–O bond formation giving rise to 118 followed by cyclization reaction and hydrolysis with moisture.

Scheme 30

Synthesis of NiIV–O2CCF3 complex 54 and C–O coupling to build the hemiketal 119. Adapted from reference [82].

Mirica and colleagues have explored C–O bond formations using O2 or n class="Chemical">H2O2 as additives. These green and environmentally friendly oxidants allow to convert the nickelacycle 120 to high-valent Ni complexes, eventually acting as coupling partners (Scheme 31) [79]. NMR and GC-MS monitoring for the oxidation of 120 with O2 permitted the quantification of the reaction products 121 (protonolysis), 21 and 122-124 (C–C and C–O couplings, respectively). The NiIV-hydroperoxo 125, the NiIV-hydroxo 126 and the hydroxylated NiIII(cyclo-neophyl) species 128 were identified using cryo-ESI-MS that suggested their participation in the C–O bond forming reactions.

Scheme 31

C–O bond formation enabled by high-valent Ni species 125, 126, and 128 generated from the NiII precursor 120 and O2 or H2O2 as oxidants. Adapted from reference [79].

4. C–H Bond Activation and/or Functionalization Enabled by High-Valent NiIII and NiIV

Direct C–H functionalization is preferred over the use of pre-functionalized substrates in view of reduced-waste production, at the same time the less activated C–H bonds makes these reactions more challenging [109,110,111]. Electrophilic substitution, which works pretty smart when using PtII and n class="Chemical">PdII catalysts fails for NiII and new approaches have focused on either NiI or high-valent NiIII or NiIV for this C–H activation. Remarkable efforts have been made in recent years on Ni-catalyzed C–H bond activation and functionalization enabled by directing groups, commonly requiring the use of sacrificial oxidants [112,113]. From a mechanistic point of view, most recent work by Chatani [14,15] and Ackermann [16,17] suggested a first C–H bond activation step enabling the formation of stable cyclometallated NiII species followed by a C–C or C–heteroatom coupling step from an in situ generated high-valent Ni species. Thus, there is current mechanistic debate dealing with the involvement of either NiI/NiIII or NiII/NiIV redox scenarios; different pathways were found viable by both computational and experimental methods [114,115,116,117,118,119]. However, reports elaborating on the isolation/identification of high-valent Ni species participating in C–H bond functionalization are very rare [120].

In 2016, the involvement of NiIII species in oxidative C–H bond activation and functionalization was demonstrated (Scheme 32) [88]. A family of stable n class="Chemical">NiIII complexes bearing the tetradentate pyridinophane ligand () were prepared and characterized. The NiIII complexes 130 and 68 underwent aromatic cyanoalkylation assisted by an intramolecular (CF3 ligand in 130) or external (KOBu in 68) base that cleaves the C(sp3)–H bond. EPR monitoring and radical trap experiments pointed to the intermediacy of NiIII species 131 and 132. These transient NiIII species are formed through: i) deprotonation of MeCN to afford the ketenimine moiety in 131; and ii) ketenimine redistribution giving access to 132. The cyanoalkylated product is finally released via reductive elimination from 132.

Scheme 32

C–H bond cyanomethylation promoted by NiIII. Adapted from reference [88].

Chatani carried out oxidative C–heteroatom couplings of quinoline-substituted amides catalyzed by n class="Chemical">Ni and suggested the participation of either NiIII or NiIV intermediates [121]. Shortly after, Sanford and co-workers successfully prepared cyclometallated σ-alkyl and σ-aryl NiII complexes that were evaluated in C(sp3)–N or C(sp2)–I couplings upon oxidation with molecular I2 [122]. High-valent σ-aryl-NiIII species are reachable upon 1e− oxidation with silver salts, but failed to achieve the C(sp2)–I coupling. On the contrary, the σ-alkyl NiIII complex 136 was isolated in 91% yield, was fully characterized using NMR and XRD, and gave rise to the β-lactam 135 via C(sp3)–N cyclizative coupling (Scheme 33) [122]. Nevertheless, harsh conditions were required and 136 resulted inactive under catalytic conditions.

Scheme 33

Access to cyclometallated σ-alkyl NiIII complex 136 and synthesis of the β-lactam 135. Adapted from reference [122].

C(sp2)–H functionalization enabled by high-valent n class="Chemical">Ni compounds has been reported by Ackermann (Scheme 34) [123]. They carried out a nickellaelectro-catalyzed C(sp2)–H bond alkoxylation of aminoquinoline-based substrates such as 137, and provided support for: i) the NiIII-mediated C(sp2)–OR coupling in presence or absence of electricity; and ii) the catalytic performance of the cyclometallated σ-aryl NiIII 138. This NiIII 138 was obtained in 39% yield upon electrolytic oxidation from [Ni0(COD)2] and 137, and was characterized using XRD and cyclic voltammetry (easy over-oxidation at 0.50 V vs. Fc0/+).

Scheme 34

Synthesis of the σ-aryl-NiIII intermediate 138, and 138-enabled C(sp2)–OPr bond formation in the presence or absence of electricity. Adapted from reference [123].

Mechanistic studies consisting of radical trap and competition experiments, evaluation of kinetic isotope effects and DFT-analysis pointed to: i) facile C(sp2)–H bond scission; ii) involvement of radicals; and iii) n class="Species">C(sp2)–OR coupling occurring from a transient formally σ-aryl NiIV key intermediate, which is better described as a ligand centered radical NiIII species [123]. In short, the NiIII complex 138 constitutes the first isolated high-valent Ni species enabling C(sp2)–H functionalization under stoichiometric and catalytic conditions [14,15,16,17,18,19,114,115,116,117,118,119].

An original ligand design strategy was employed to accomplish the C–H bond nickelation of n class="Chemical">arenes and alkanes induced by N-fluoro-2,4,6-trimethylpyridinium triflate (NFTPT; Scheme 35) [124,125]. The identity of the NiIV platforms 142a–c and 144-X was corroborated using NMR and XRD. The decisive role of triflate to assist the C–H to C–NiIV bond conversion was demonstrated through the isolation of 143a when the triflate was replaced by tetrafluoroborate. A NiIV-driven C–H bond nickelation was found to be the preferred pathway by computational means (vs. the competing NiIII-mediated path). Reaction of isolated 144-OTf with external nucleophiles 146a-h led to the C–Nu coupled products 146a–h, thereby ascertaining its capacity to promote C–C and C–heteroatom bond forming processes.

Scheme 35

C–H bond breaking/C–NiIV bond forming sequence via NiII/NiIV redox manifold and C–C and C–heteroatom couplings mediated by 144-OTf. Adapted from references [124,125].

Our group has contributed to the field of C(sp2)–H bond functionalization and performed aromatic trifluoromethylations enabled by high-valent n class="Chemical">NiIII-CF3 and NiIV-CF3 compounds named 149, 149-py, and 148, respectively (Scheme 36) [126]. These high-valent species are: i) stabilized by simple, monodentate ligands (py, CF3, and F-itself); ii) easily accessible from identical sources (i.e., [(py)2NiII(CF3)2] (147) and XeF2); iii) remarkably stable (isolable); and iv) authenticated using XRD and EPR (149, 149-py) or XRD and NMR (148). Both NiIII-CF3 and NiIV-CF3 species underwent the C–H bond breaking/C–CF3 bond forming sequence of arenes (1,2-dichlorobenzene or pyridine) with excellent yields (up to 94%) and intriguing selectivity.

Scheme 36

Synthesis of NiIV-CF3 148 and use in C(sp2)–H bond trifluoromethylation of arenes. Adapted from reference [126].

The group of Sanford has isolated and fully characterized the NiIV-n class="Chemical">CF3 complex 76 (Scheme 37) [127], which is the first NiIV species bearing three CF3 groups. Assisted by the Tp ligand, 76 reacts in a stoichiometric fashion with 2,4,6-trimethoxybenzene (TMB) to yield the corresponding benzotrifluoride TMB–CF and the NiII-CF3 complex 22-H, which was in situ re-oxidized to 76 by 150. Most remarkably, 76 represents the first authenticated NiIV catalyst for the C(sp2)–H bond trifluoromethylation of (hetero)arenes (turnover number (TON) up to 5), including the industrially relevant scaffolds tadalafil, melatonin or boc-L-tryptophan [127]. Mechanistic studies supported the involvement of ●CF3 radicals and NiII-CF3, NiIII-CF3 and NiIV-CF3 intermediates.

Scheme 37

Synthesis of the catalytically efficient [(Tp)NiIV(CF3)3] (76) via NiII/NiIV redox manifold. Adapted from reference [127].

Company and co-workers have synthesized the NiIII-oxyl complex 152 [ and the high-valent compounds n class="Chemical">NiIII-Cl 153 and NiIII-OCl 154 by reaction of the tetraaza-NiII precursor 151 and meta-chloroperbenzoic acid (HmCPBA) and CaOCl + acetic acid [129], respectively (Scheme 38). The structures of 152–154 were ascertained by exhaustive spectroscopic characterization and DFT-calculations. This work has demonstrated the ability of the NiIII-oxyl 152 and the NiIII-OCl 154 to promote C(sp3)–H bond oxidation of organic substrates.

Scheme 38

Synthesis, characterization and reactivity of high-valent NiIII species 152–154. Adapted from references [128,129].

A dinuclear NiIII complex participating in C–H bond activation and the ensuing C–C or C=O bond forming reactions were published by Morimoto, Itoh and co-workers [130]. The n class="Chemical">NiIII species 156 bearing the triazadentate ligand dpema was synthesized by treatment of the NiII precusor 155 with H2O2 in acetone at −90 °C (Scheme 39) [130]. Anion exchange with NaBPh4 permitted the selective crystallization of 156 that was appropriately characterized (XRD, EPR, magnetic measurements (Superconducting Quantum Interference Device (SQUID)), Raman, and ESI-MS). The keen analysis of 156 demonstrated the unprecedented triplet ground state for a high-valent [M2(μ-O)2] core, along with the ferromagnetic coupling of the NiIII centers. In addition, 156 mediated the selective C–H bond functionalization of 2,4-di(tert-butyl)phenol (157) or xanthene (158) yielding 159 and 160, respectively.

Scheme 39

Synthesis and full characterization of the NiIII dimer 156, and its use to mediate C–H bond oxidation of phenols and activated alkanes. Adapted from reference [130].

A dinuclear NiIV that mediates C–H bond functionalization was synthesized and characterized by Swart and n class="Chemical">Browne (Scheme 40) [131]. The complex [(Me3tacn)NiIV(μ-O)3]2+ (162), attained from the dinuclear NiII complexes 161a,b and NaOCl, represents a rare example of an isolated dinuclear NiIV complex. Its structure was determined by NMR, Raman spectroscopy (labelling experiments), XANES, XES, ESI-MS, and computational data. The C–H functionalization mediated by 162 proved viable for several substrates (methanol, xanthene, 9,10-dihydroanthracene, and fluorene).

Scheme 40

Synthesis of the dicationic [(Me3tacn)NiIV(μ-O)3]2+ complex 162 and oxidation of methanol to formaldehyde enabled by 162. Adapted from reference [131].

5. Miscellaneous

Other interesting transformations dealing with high-valent Ni complexes that are involved in cross-coupling events and bond forming reactions are disclosed in this section. Hereafter, a short selection of cyclization reactions, C–heteroatom or n class="Chemical">N–N bond forging reactions, and olefin functionalization mediated by NiIII or NiIV are collected.

A first example is constituted by the 141-catalyzed synthesis of heterocyclic salt [164][Cl] (Scheme 41) [125]. In this work, the functionalized n class="Chemical">bipyridine 163 was converted to [164][Cl] in 76% yield upon mild heating in presence of [NMe4][Cl], NFTPT (excess) and 20 mol% of NiII-CF3 catalyst 141 (TON ca. 4). The viability of a NiII/NiIV redox scenario was strongly supported by the stoichiometric reaction of 144-OTf with chloride anions that provided the heterocyclic salt [164][X] (X= Cl, OTf) in nearly quantitative yield.

Scheme 41

C(sp3)–H bond breaking/C(sp3)–N bond forming sequence via NiII/NiIV catalysis. Synthesis of the heterocyclic salt [164][X]. Adapted from reference [125].

Diao and co-workers discovered the N–n class="Chemical">N coupling of the guanidine derivative triazabicyclodecene (TBD) starting from the NiII complex 165 and PhICl2 (Scheme 42) [132]. Addition of PhICl2 (0.5 equivalents) to 165 at low temperature allowed the isolation and characterization of the NiII-NiIII-Cl mixed valence compound 167. The trans-influence of the chloride ligand in 167 prevented Ni–Ni bond interactions giving rise to a rare NiII-NiIII-Cl homobimetallic complex with a zero order Ni–Ni bond. The isolated material 167 resulted to be coupling inactive. In the presence of PhICl2, 167 underwent instantaneous N–N bond formation involving an elusive Cl-NiIII-NiIII-Cl species 168, which is reminiscent of Ritter’s PdIII chemistry [98].

Scheme 42

N–N bond formation from an assumed NiIII–NiIII species 168, generated from the mixed valence compound 167 and PhICl2. Adapted from reference [132].

An indazole scaffold was synthesized in high yield by Vicic and co-workers from the perfluorinated n class="Chemical">metallacycle 169 in presence of mild oxidant, base and a fluoride source (Scheme 43) [133]. Once isolated and conveniently characterized (NMR and EA), the isolated NiIVF2 172 underwent N–N cyclizative coupling upon addition of 173 and pyridine to build 170. The formation of 170 requires: i) coordination of 173 to 172; ii) deprotonation of the N–H moiety ligated to NiIV; and iii) R.E. step and recovery of the NiII(C4F8) fragment.

Scheme 43

Isolable NiIVF2 172 and its capacity to promote N–N bond forming processes. Adapted from reference [133].

The imido transfer reaction from M=NR fragments to organic substrates represents an innovative approach to build C–n class="Chemical">N bonds. In this sense, Warren disclosed the synthesis of the NiIII-imido complex 174 by reacting the NiI precursor 173 with adamantylazide (AdN3 in Scheme 44) [134]. The NiIII=NAd complex was isolated in 52% yield and studied using XRD, EPR, and DFT-calculations. The imido-group transfer from 174 proved viable towards CO and CNBu yielding cumulenes 175 and 176 in high yields.

Scheme 44

Imido-group transfer reactions mediated by the NiIII=NAd complex 174. Adapted from reference [134].

van Koten performed Kharasch additions involving aryl-NiIII n class="Chemical">pincer complexes allowing for the double functionalization of olefins [135,136,137,138,139,140,141]. Mechanistic studies (IR, EPR, and NMR) using the aryl-NiII 177 pointed to the participation of mononuclear aryl-NiIII intermediates (Scheme 45) [135,136,137,138,139,140]. The C–halogen bond scission and concomitant NiII to NiIII oxidation was found to be the rate determining step of the catalytic cycle [138]. Later, the same group isolated and characterized (XRD, EPR, and EA) the aryl-NiIIICl2 species 178 by reacting the corresponding aryl-NiII-Cl complex and CCl4, thus proving right their initial hypothesis [140]. Zargarian isolated the catalytically active NiIIIX2 complexes 179 and 180a–c bearing bis(phosphinite) (POCOP) or phosphinite-amine (POCN) based pincer-type ligands (Scheme 45) [141,142,143]. The novel NiIII platforms were authenticated using diverse techniques (including XRD), and mediated catalytic Kharasch additions.

Scheme 45

Ni-pincer complexes involved in Kharasch addition reactions [135,136,137,138,139,140,141,142,143].

6. Summary and Conclusions

The study of fundamental organonickel chemistry and the use of n class="Chemical">nickel complexes in organometallic catalysis represent a jointly emerging research field. The main reasons are: i) the higher abundance and lower price of Ni compared with 4d and 5d metals; ii) the very rich and diverse redox reactivity of organonickel compounds; and iii) its enhanced reactivity that provides more room for reaction discovery. However, the air and moisture sensitivity of Ni-compounds and their propensity to undergo single electron transfer (SET) processes makes the mechanistic elucidation more challenging. This is particularly true for the commonly invoked, yet rarely proved, involvement of high-valent organonickel species in catalytic reaction mechanisms, including the highly demanded cross-coupling reactions. Here, the appropriate design of the ancillary ligand plays a pivotal role in improving the stability of NiIII and NiIV complexes, thus allowing for their characterization and the discovery of their unprecedented reactivity. In this sense, this review aims to provide a general overview of most common strategies to successfully stabilize coupling active high-valent Ni species, namely: i) the coordination of polydentate N-donor ligands (Tp, Py3CH, pyridinophane derivatives…); ii) the incorporation of nickelacyclic cores; or iii) the use of strong σ-donating perfluorinated ligands (CF3 or the C4F8 fragment).

On the other hand, most representative work enclosed in the field of cross-coupling reactions enabled by spectroscopically characterized NiIII and n class="Chemical">NiIV compounds are herein disclosed [144,145]. As a representative example, while low-valent Ni catalysts perform well for classical cross-coupling events, the intermediacy of high-valent Ni compounds becomes necessary in order to achieve more challenging transformations such as the C–F or C–CF3 bond-forming reactions. In addition to their enhanced activity, distinct reactivity patterns are displayed quite frequently by high-valent organometallic compounds. This was perfectly illustrated by the efficient C(sp3)–heteroatom coupling found for the NiIV platforms 50 and 52 instead the more favorable C(sp2)–heteroatom bond formation, commonly mediated by low-valent Ni compounds.

The study and deep understanding of the elementary reactions occurring for the high oxidation states of NiIII or n class="Chemical">NiIV permitted to broaden the scope of transformations enabled by NiIII and NiIV species. The current State of the Art for NiIII and NiIV mediated bond forming reactions includes: i) C–C and C–heteroatom bond formation; ii) C–H bond functionalization; and iii) alternative N–N and C–heteroatom couplings. Most remarkably, the first two approaches to NiII/NiIV catalysis have been reported recently and allowed for the C–H bond trifluoromethylation of industrially-relevant (hetero)arenes and C–N cyclization reactions. With no doubt, future work will expand the array of transformations mediated by NiIII and NiIV species, and more catalytic applications mediated by a NiII/NiIV redox scenario will appear soon.