Nickel-Catalyzed C–F bond Activation

Scheme 1.3. Conversion of SPOs to PAs.

Owing to the increased synthetic utility, a variety of synthetic pathways to prepare achiral aryl,^[52] alkyl^[53] and ferrocenyl^[54] SPOs as well as chiral (R,R)-TADDOL,^[55] (S,R_p )-DIAPHOX,^[56] JoSPOphos^[57] and P-stereogenic^[58] SPOs were developed. Depending on the affinity of the metal center towards the soft phosphorus or the hard oxygen atom, a number of different coordination modes can be observed.^[59] In general, early transition metals coordinate through the hard oxygen atom and late transition metals prefer the soft phosphorus atom (Scheme 1.4).^[60] In addition, metals with both types of coordination have also been reported.^[61]

Scheme 1.4. Main coordination modes of SPOs and PAs.

1.3. Nickel-Catalyzed C–F bond Activation

While many cross-couplings rely on palladium catalysts, earth abundant 3d metals or main group elements are in terms of costs and availability more attractive.^{[22b, 62]}

Especially nickel, as the “impoverished younger sibling of palladium” shows important features,^[63] such as highly reactive organometallic species and a variety of accessible oxidation states, within synthetically useful reaction conditions (Figure 1.3). Based on this, nickel is considered as an excellent candidate for reactions involving unreactive electrophiles and reactions involving single electron transfers.^[64] As a result, numerous applications in synthetic and green chemistry were developed involving the activation of even unreactive C(aryl)–O and C(aryl)–F bonds.^[65]

Figure 1.3. Properties of nickel and palladium in cross-coupling chemistry.

Inspired by the Barbier reaction,^[66] Victor Grignard discovered in 1900 the formation of organomagnesium halides,^[67] extremely valuable and important synthetic tools,^[68] that set the stage for one of the first successful combinations of organometallic reagents within catalysis by using NiCl2 in 1924 (Scheme 1.5a).^[69] Following these discoveries, Kharesash developed in 1941 the metal-catalyzed homo-coupling of organomagnesium reagents.^[70] Interestingly, the study was focused on earth-abundant 3d metals, such as CoCl2, MnCl2, FeCl2 and NiCl2, and showed already the first reported catalytic cross-coupling, by using vinyl bromide and phenylmagnesium bromide (Scheme1.5b).^[71]

Scheme 1.5. Early studies in nickel-catalyzed coupling reactions.

Studies by Kumada^[11a] and Corriu^[11b] resulted in the nickel-catalyzed cross-coupling reaction of Grignard reagents with aryl halides, currently known as the Kumada-Corriu reaction, and showed the important effect of additional phosphine ligands within the catalysis (Scheme 1.6a).^[72] As an extension, Kumada achieved the C–F activation under nickel catalysis, using NiCl2(dmpe), fluorobenzene 11a and isopropylmagnesium chloride.^[73] Unfortunately the facile β-hydride elimination resulted in a predominant isomerization of the secondary alkyl group (Scheme 1.6b). Even though the development of functional group tolerant nucleophiles and the use of (pseudo)halides marked a great milestone in cross-coupling reactions,^[15] it took almost 25 years until the unique

1.3. Nickel-Catalyzed C–F bond Activation

Schema 1.6. Pioneering studies in nickel-catalyzed cross-couplings using alkyl magnesium halides 9.

In 2001, the group of Herrmann showed that the nickel NHC complex 14 catalyzed the reaction between aryl fluorides 11 and Grignard reagent 1a to generate biaryls (Scheme 1.7a).^[74] The catalytically active species is thought to be a nickel(0) species coordinated by a sole NHC ligand. During the same time, Perutz and Braun reported the first catalytic cross-coupling reaction of polyfluorinated arenes (Scheme 1.7b).^[75] Using a pre-formed nickel(II)-fluoro-phosphine complex 18, a Stille-type coupling was achieved.

Scheme 1.7. Nickel-catalyzed C–F activation by well-defined (a) NHC and (b) cyclometalated complexes.

The importance of the ligand design in nickel catalysis was showcased by a push-pull strategy for nickel-catalyzed cross-coupling reactions of aryl fluorides with Grignard reagents by Nakamura (Scheme 1.8).^[76] Through careful ligand design, the hydroxyphosphine ligand 23 was able to facilitate C(sp²)–F arylations. DFT calculations and mechanistic experiments indicated that the reaction proceeded through a nickel–

magnesium bimetallic manifold, that reduces nickel(II) to nickel(0) upon deprotonation of the P–OH ligand.

Scheme 1.8. Hydroxyphosphine ligand 23 for nickel-catalyzed C–F activation.

Studies by Ackermann were based on air-stable secondary phosphine oxides (SPO) for the activation of C(aryl)–F bonds. In 2005, Ackermann reported the first use of air-stable SPOs for the activation of C–F bonds. The sterically congested diaminophosphine oxide pre-ligand 26 showed excellent activity at ambient temperature, furnishing numerous biaryl scaffolds (Scheme 1.9a).^[77] Furthermore, Ackermann introduced in 2010 the sterically congested pre-ligand 29 which showed excellent reactivity with a variety of (hetero)arenes at ambient temperature and exclusively yielded monosubstituted products 30, highlighting the synthetic utility of SPOs in nickel catalysis (Scheme 1.9b).^[78]

Scheme 1.9. Nickel/SPO catalysis for C–F activation.

Following these initial reports, it was demonstrated that numerous organometallic reagents in terms of arylation,^[79] alkylation^[80] and alkynylation^[81] among others^[82] were suitable for C–F coupling reactions. Furthermore, the introduction of directing groups

1.3. Nickel-Catalyzed C–F bond Activation nickel-catalyzed Suzuki–Miyaura cross-coupling reaction using zirconium tetrafluoride as co-catalyst or a N-containing directing groups (Scheme 1.10).^[83] A variety of functional groups and substituents were tolerated and a change in the turnover-limiting step, from oxidative addition to transmetalation, upon the introduction of directing groups, was observed. It is assumed that zirconium tetrafluoride acts as a LEWIS-acid to facilitate the elimination of the fluorine-atom in an oxidative addition and/or transmetalation process.

Scheme 1.10. C–F activation enabled by a LEWIS-acid or directing group.

Even though many methods were developed generating C(sp²)–C(sp³) bonds with secondary or tertiary alkyl (pseudo)halides,^{[17a, 84]} only selected examples showed homologous transformations with secondary and tertiary alkyl nucleophiles and are mostly restricted to reactive aryl halides.^[85] Generally, these protocols rely on the use of highly electron-rich and sterically congested ligands around the metal center to promote fast reductive elimination, thus enhancing selectivity. In terms of nickel-catalyzed C–F activation, the use of branched nucleophiles is especially challenging with respect to selectivity, due to the preferred β-hydride elimination.^[86] In this context, Cornella reported in 2018 on a strategy based on a unique nickel catalyst, which circumvents some of the afor-mentioned obstacles (Scheme 1.11).^[87] The synthetic efficacy was attributed to the beneficial effect of the gem-dialkyl substitution on the ligand 35, after observing a correlation between the P-Ni-P angle and the chemoselectivities for secondary alkyl nucleophiles.

Scheme 1.11. C–F activation with branched alkylmagnesium halide 9.

An approach that gained recent attention is the metal-mediated and -catalyzed elimination of α- or β-fluorine atoms, due to milder conditions that are required compared to the oxidative addition into C–F bonds that represents an organometallic C–F activation.^[88]

Transformations through these elimination processes typically proceeded by carbon–

carbon or carbon–heteroatom bond formations and were increasingly developed as C–F bond activation methods.^[89] The first example of such an elimination approach was reported in 1991 by Heitz, who showed the transition metal-catalyzed activation of a C–F bond by β-fluorine elimination to afford α-fluorostyrenes 41 (Scheme 1.12).^[90]

Schema 1.12. Early example of palladium-catalyzed C–F activation by β-fluorine elimination.

Taking inspiration from this work, Loh and Feng developed a Rh(III)-catalyzed C–H and C–F activation, based on β-fluorine elimination, to generate fluorovinylated heterocycles.^[91] At the same time, Ackermann^[92] among others^[93] showed that 3d metal catalyst are also well suitable for such kind of transformation. High selectivities of vinylic 44 as well as allylic 45 1,1-difluoroalkenes and the modification of 7-azaindols,^[92b]

important building blocks in pharmaceuticals,^[94] are key developments within these C–H/C–F functionalization manifold (Scheme 1.13). Although different transition metals

1.4. Nickel-Catalyzed C–H Activation for Alkene Hydroarylations