Enantioselective Nickel-Catalyzed C–H Activation

While nickel-catalyzed inner-sphere C–H activations, especially hydroarylations, are nowadays well established, asymmetric transformations remain scarce. Thus far, all known examples involve the asymmetric functionalization of alkenes.^[52]

Taking inspiration from previous works by Nakao and Hiyama,^[169] Cramer reported an enantioselective nickel-catalyzed intramolecular hydrocarbamoylation of homoallylic formamides 113 (Scheme 1.37).^[195] In this context, it should be mentioned that (C=O)–H activations have been accomplished with a broad range of

catalysts, with the hydroacylations of alkenes and alkynes being extensively documented.^[196] A significant fraction of formyl C–H activations has been proposed to occur through radical mechanisms,^[31a] taking advantage of the low bond dissociation energy (BDE) of the formyl C–H bond.^[28] The chiral heteroatom-substituted secondary phosphine oxide^[197] (HASPO) 114 preligand developed by Cramer enabled the asymmetric synthesis of pyrrolidinones 115, featuring a Ni/Al^[198]

heterobimetallic^[23b] activation mode. While a nickel catalyst solely prepared from the chiral SPO performed poorly, the addition of a co-catalytic amount of phosphine led to an increased efficacy, presumably by assisting the displacement of the cod ligand from the precatalyst. This work is truly remarkable as it represents the first enantioselective transformation by inner-sphere C–H activation with a 3d transition metal catalyst.^[52]

Scheme 1.37. Enantioselective intramolecular nickel-catalyzed hydrocarbamoylations of alkenes.^[195]

A reasonable catalytic cycle was proposed to begin with the formation of the Al/SPO adduct 116, a bifunctional ligand whose aluminium center retains its Lewis acidity while the Lewis basic phosphorous atom can coordinate to the nickel center (Scheme 1.38). The aluminium center then activates the carbonyl group of 113, providing intermediate 118. Thereafter, oxidative of the C–H bond on nickel generates the six-membered hetero-bimetallacycle 119. Migratory insertion then leads to complex 120, and reductive elimination releases lactam 115 and regenerates the heterobimetallic catalyst 117. This mechanism was further supported by the independent synthesis of the Lewis acid/SPO adduct 116, which

was found to promote the cyclization with excellent yield and enantioselectivity without additional AlMe3 or PPh3.

Scheme 1.38. Plausible mechanism of the nickel-catalyzed hydrocarbamoylation.^[195]

As previously mentioned, Nakao and Hiyama developed an intramolecular C–H alkylation of pyridones with unactivated tethered alkenes using a nickel-P(iPr)3

catalytic system in the presence of AlMe3.^[167] Inspired by these results, Cramer subsequently developed a ligand-controlled regiodivergent annulation of pyridones 121, with IPr giving selectively the endo-cyclized product, while the exo-product was obtained with cod as the ligand.^[193] Preliminary efforts towards an asymmetric version of this reaction were also disclosed (Scheme 1.39a). The chiral NHC ligand

122, based on the design of Hong and coworkers,^[199] provided the endo-cyclized products 123 in 78.5:21.5 e.r.

Scheme 1.39. Enantioselective nickel-catalyzed hydroarylation with pyridones.^[193,200]

Further investigations by Cramer on the asymmetric cyclization of pyridones with tethered olefins led to the discovery of the novel chiral NHC 125, inspired from a previous ligand design by Gawley^[201] with a modified acenaphthene backbone (Scheme 1.39b).^[200] Under the optimized reaction conditions, the endo-cyclized annulated pyridones and uracils 126 were obtained from diversely decorated alkenes 124 in excellent yields and enantiomeric excesses at mild reaction temperatures in the presence of MAD. Based on literature precedents,^[202] the authors proposed the C–H cleavage step to occur through a LLHT manifold. This approach was later extended to pyridines 127 by Shi under similar reaction

conditions (Scheme 1.40).^[203] Thus, the corresponding tetrahydro(iso)quinolines 129 were obtained with excellent diastereo- and regio-selectivities.

Scheme 1.40. Enantioselective nickel-catalyzed hydroarylation with pyridines 127.^[203]

Following the elegant studies of Bergman and Ellman,^[204] the undirected cyclization of azoles with tethered alkenes has long been dominated by rhodium(I) catalysts, with a notable exception by Cavell for the nickel-catalyzed cyclization of highly activated (benz)imidazolium salts.^[205] In this context, Ye reported on the unprecedented nickel-catalyzed enantio- and exo-selective hydroarylation of olefins 130 with tethered imidazoles (Scheme 1.41).^[206] The TADDOL-derived HASPO preligand 131 enabled a nickel-aluminum bimetallic catalysis. Such TADDOL-HASPOs had previously been exploited in asymmetric organocatalysis,^[207] but their use in enantioselective transition-metal catalysis had remained rare.^[208] Thus, diverse polycyclic azoles 132 with β-stereocenters were obtained in outstanding yields and enantioselectivities. Interestingly, sensitive functional groups, including bromo-substituents, as well as diversely substituted alkenes, proved viable in the nickel catalysis.

Scheme 1.41. Asymmetric nickel-catalyzed exo-selective hydroarylation of alkenes 130.^[206]

In analogy to the hydrocarbamoylation presented above (Schemes 1.37–1.38), a plausible catalytic cycle begins with the formation of an Al/SPO adduct, which can coordinate the nickel precursor to deliver complex 133 (Scheme 1.42). Then, through a heterobimetallic mode of activation, the aluminium center can be coordinated by the imidazole’s nitrogen, while the nickel center binds the alkene to give intermediate 134. The authors suggested the C–H cleavage step to occur through a direct LLHT from the imidazole to the olefin, but an oxidative addition pathway could not be entirely ruled out.

Scheme 1.42. Proposed mechanism of the asymmetric nickel-catalyzed exo-selective hydroarylation.^[206]

While nickel-catalyzed intramolecular asymmetric hydroarylations have been recognized as a powerful tool for the synthesis of important polycyclic bioactive scaffolds, enantioselective intermolecular versions remain hitherto largely unknown.

In 2011, Fukuzawa disclosed an elegant nickel/NHC-catalyzed three-component reaction between benzaldehydes 138, norbornenes 137, and silanes 139 leading to polycyclic indanols 141.^[209] Thereafter, Cramer designed the chiral NHC ligand 140 to achieve this transformation in an enantioselective fashion (Scheme 1.43).^[210]

Interestingly, while the flanking N-aryl substituents of Grubbs-type chiral NHCs^[211]

have been extensively investigated, modifications of the chiral backbone remain underexplored. This transformation allowed for the expedient diastereoselective synthesis of annulated indanols 141 bearing five contiguous stereocenters.

Scheme 1.43. Nickel-catalyzed asymmetric reductive three-component coupling.^[210]

Despite significant progress in very recent years with non-noble metals,^[52] such as nickel[193,200,203,206]

and cobalt^[106] (Schemes 1.13, 1.19, 1.39–1.41), enantioselective hydroarylation-type C–H activations^[23i] remain vastly dominated by costly noble 4d and 5d transition metals, such as iridium^[212], rhodium,^[213] and others,^[214] or rare-earth complexes.^[215] Therefore, the development of new chiral catalysts based on earth-abundant, inexpensive and less-toxic 3d transition metals is highly desirable.