Ligand Relay Catalysis Enables Asymmetric Migratory Hydroarylation for the Concise Synthesis of Chiral α‐(Hetero)Aryl‐Substituted Amines

Abstract Complementary to the design of a single structurally complex chiral ligand to promote each step in transition‐metal catalysis, multiligand relay catalysis through dynamic ligand exchange with each step in the catalytic cycle promoted by its best ligand provides an attractive approach to enhance the whole reaction reactivity and selectivity. Herein, a regio‐ and enantioselective NiH‐catalyzed migratory hydroarylation process with a simple combination of a chain‐walking ligand and an asymmetric arylation ligand, producing high‐value chiral α‐(hetero)aryl‐substituted amines and their derivatives under mild conditions, is reported. The potential synthetic applications of this transformation are demonstrated by the concise synthesis of (S)‐nicotine and a CDK8 inhibitor.


Introduction
As a structural motif, enantioenriched -(hetero)aryl-substituted amines and their derivatives widely exist in various natural products, pharmaceuticals, and catalysts (Figure 1a). [1]Starting from activated functionalized alkene starting materials, asymmetric hydroamination [2,3] and hydroarylation [4] catalyzed by metalhydride, especially by nickel-hydride or copper-hydride, are two DOI: 10.1002/advs.202306447attractive approaches for the efficient synthesis of -(hetero)aryl-substituted amines and their derivatives [5] (Figure 1b).In these two processes, with a stoichiometric amount of hydrosilane, styrenes [2,3] or protected (acyl or carbamate) enamines [4] are used as latent alkyl carbanion equivalents through the catalytic generation of alkylcopper or alkylnickel intermediates, avoiding the pre-generation of organometallic reagents.However, in terms of olefin starting materials, the need to prepare activated functionalized alkenes in asymmetric hydrofunctionalization reactions [6,7] is still less than ideal.It would be ideal if the unactivated alkenes which generally are commercially available or more easily prepared.We recognized that if asymmetric migratory hydrofunctionalization could be achieved, [8][9][10][11] unactivated remote alkenes or isomeric mixtures of alkenes would be suitable starting materials, generating the required alkylnickel species in situ through chain-walking to participate in the subsequent asymmetric functionalization.
However, in NiH-catalyzed asymmetric remote functionalization, the design of a single chiral ligand to promote both chain-walking and subsequent asymmetric coupling is highly challenging. [11]Recently, a synergistic combination of two structurally simple ligands, one for chain-walking and the other for asymmetric coupling, ligand relay catalysis [12] through dynamic ligand exchange provides a particularly appealing approach to address this regio-and stereochemical challenge in this area.We hypothesized that asymmetric migratory hydroarylation [10,13] might analogously be realized using our ligand relay catalytic strategy, thereby allowing access to chiral -(hetero)aryl-substituted amines from unactivated remote alkenes or their isomeric mixtures (Figure 1c).Specifically, with a suitable chain-walking ligand (L) to generate a series of alkylnickel species along an alkyl chain, the subsequent regio-and enantioselective arylation could be realized efficiently and selectively with an appropriate asymmetric arylation ligand (L*).A suitable ligand combination must fulfill a number of requirements.First, chain-walking ligandpromoted isomerization between alkylnickel isomers must be rapid compared to subsequent arylation.Second, to avoid the racemic background reaction in the arylation step, the chainwalking ligand or ligandless background reactivity must be relatively low.Third, asymmetric arylation promoted by the chiral ligand must be highly regio-and enantioselective.In this work, we describe a high regio-and enantioselective Nicatalyzed hydroarylation process enabled by a ligand relay catalysis strategy under exceptionally mild conditions.A wide variety of enantioenriched -(hetero)aryl-substituted amines and their derivatives were obtained in high yields with well control of both rr and ee.The utility of this protocol is illustrated by the concise three-step synthesis of (S)-nicotine and a CDK8 inhibitor.

Results and Discussion
To test our hypothesis, the asymmetric migratory hydroarylation reaction of N-(but-3-en-1-yl)benzamide (1a) and methyl 4bromobenzoate (2a) was chosen as the model reaction under a combination of a chain-walking ligand and an asymmetric arylation ligand (Table 1).Systematic optimization revealed that both the regioselectivity and enantioselectivity could be well-controlled with a combination of a chain-walking phenanthroline ligand (L1) and an asymmetric arylation biimidazoline (BIIM) ligand (L1*), delivering product 3a in 72% isolated yield with a 97:3 regioisomeric ratio (rr) and 92% enantiomeric excess (ee) (Table 1, entry 1).In line with our expectations, both ligands are necessary for this migratory asymmetric arylation, and essentially no desired product formation was observed when either ligand was omitted (entries 2 and 3).Decreasing the loading of chainwalking ligand to 0.3 mol% led to somewhat lower regioselectivity (entry 4).An alternative chain-walking ligand (L2) was found to be considerably less effective than L1 (entry 5).On the other hand, a chiral BIIM (bisimidazoline) ligand (L1*) turned out to be generally more effective on both reactivity and enantioselectivity than that with a BiOx (bi-oxazoline) scaffold (entry 6).Reducing the loading of nickel salt to 0.5 mol% (same amount of L1) led to low conversion (entry 7).This preliminary result indicates that the required chiral ligand (L1*) ligated N-protected -amino alkylnickel(I) species is mainly obtained through reversible transmetallation between alkylnickel(II)L1 species and nickel(I)L1* species (L1*Ni I I or L1*Ni I H). [14]The use of a different nickel source (NiBr 2 •DME) or a silane source (diethoxymethylsilane) led to a slightly diminished yield (entries 8, 9).Interestingly, by changing the cation of a base from sodium to potassium (K 2 CO 3 or K 3 PO 4 ), the L1-promoted background arylation reaction could be enhanced, resulting in only moderate ee (entries 10 and 11).The addition of a catalytic amount of iodide salt could facilitate the chain-walking process, resulting in better yield and rr (entries 1, 12 vs entry 13).Screening of solvents revealed that a single solvent led to either complete failure of the reaction (entry 14) or a diminished yield (entry 15). [15]Notably, a slightly lower yield was observed when using the more reactive aryl iodide as an electrophile (entry 16).
Not limited to alkene-contained acyclic amines, our protocol was applicable across many commercially available Ncarbamate protected heterocyclic alkene substrates, affording corresponding biologically important enantioenriched -(hetero)aryl-substituted N-heterocycles as a single regioisomer in good yields with excellent ee (Figure 3).Unfortunately, sixmembered N-heterocyclic alkenes did not participate in the desired arylation event, with substantial amounts of the alkene starting material being recovered.In addition to aryl bromides (6a, 6b), a wide variety of structurally diverse heteroaryl bromides (6c-6h) were also legitimate electrophiles.For example, pyridines with various substitution patterns which are commonly found in bioactive molecules, were shown to be viable substrates, delivering the chiral -heteroaryl-substituted N-heterocycles in good yields with excellent enantioselectivity (6c-6h).
A competition experiment between a 1:1 ratio of ipso-and remote alkenes was carried out (Scheme 1a).Both ipso-and migratory arylation products (3a and 3v) were obtained with similar selectivity.This result indicated that the reaction rate of chain-walking is faster than that of subsequent arylation.The ligand relay catalysis strategy could also facilitate the asymmetric ipso-hydroarylation (Scheme 1b).In contrast, lower yield and rr were obtained with a single chiral ligand.The alkene scope could also be extended to heteroatom O-substituted olefins (1w and 4i), although only moderate ee was obtained in these cases (Scheme 1c).The practicality and synthetic flexibility of the method were further illustrated by the facile synthesis of two bioactive molecules, (S)-nicotine (7) and a CDK8 inhibitor (8), from the corresponding chiral -arylated pyrrolidine cores (6d and 6b) which were successfully obtained through the key migratory hydroarylation approach from commercially available starting materials (Scheme 1d).

Conclusion
In summary, we have described herein a NiH-catalyzed asymmetric migratory hydroarylation to access both cyclic and acyclic, enantioenriched -(hetero)aryl-substituted amines and their derivatives under mild conditions.Significantly, through a key dynamic ligand exchange process, this ligand relay catalytic strategy enhances whole reaction efficiency with simultaneous control of regio-and enantioselectivity, allowing the employment of readily available unactivated remote alkenes or their isomeric mixtures as starting materials.The synthetic merits of this method were demonstrated by the facile synthesis of (S)-nicotine and a pharmaceutical agent.

Figure 2 .
Figure 2. Asymmetric migratory hydroarylation to access enantioenriched acyclic -(hetero)aryl-substituted amines.a Yield under each product refers to the isolated yield of purified product (0.20 mmol scale, average of two runs), regioisomeric ratio (rr) was determined by GC and GC-MS analysis, enantioselectivities were determined by chiral HPLC analysis.Please see Figures S1 and S2 for test tube and cap used.

Table 1 .
Variation of reaction parameters.
a) Yields determined by GC using n-dodecane as the internal standard, the yield in parentheses is the isolated yield (0.20 mmol scale) b) rr, regioisomeric ratio, represents the ratio of -arylation product (3a) to all other regioisomers, determined by GC and GC-MS analysis c) Enantioselectivities were determined by chiral HPLC analysis.Bz, benzoyl;Tol, toluene; NMP, N-methylpyrrolidone.Adv.Sci. 224, 11, 2306447