Enantioselective access to chiral aliphatic amines and alcohols via Ni-catalyzed hydroalkylations

Chiral aliphatic amine and alcohol derivatives are ubiquitous in pharmaceuticals, pesticides, natural products and fine chemicals, yet difficult to access due to the challenge to differentiate between the spatially and electronically similar alkyl groups. Herein, we report a nickel-catalyzed enantioselective hydroalkylation of acyl enamines and enol esters with alkyl halides to afford enantioenriched α-branched aliphatic acyl amines and esters in good yields with excellent levels of enantioselectivity. The operationally simple protocol provides a straightforward access to chiral secondary alkyl-substituted amine and secondary alkyl-substituted alcohol derivatives from simple starting materials with great functional group tolerance.

C hiral aliphatic amines and alcohols are widespread substructures in pharmaceutical molecules, natural products and organic materials, and serve as common chiral building blocks for other functional groups and value-added molecule synthesis [1][2][3] . Additionally, over half of small-molecule drugs are the derivatives of chiral aliphatic amines and alcohols among the top 200 best-selling drugs (Fig. 1a) 4 . Thus, the enantioselective synthesis of pure aliphatic amines and alcohols has been recognized as a long-term interest in chemistry community. Over the past decades, significant progress has been made in this field enabled by enantioselective C-H amination/ oxygenation [5][6][7][8] , addition of alkyl organometallic reagents to imines or aldehydes [9][10][11][12][13] , and hydrogenation of imines, enamines, ketones, or enol esters [14][15][16][17][18][19] . However, chiral catalysts have difficulty in identifying different faces of prochiral centers bearing two alkyl groups with similar steric and electronic properties 20 . Thus, these methods are typically applied to build chiral aliphatic amines and alcohols with the stereogenic center adjacent to aryl or carbonyl groups (Fig. 1b) 14,[21][22][23][24] . To control the enantioselectivity of asymmetric reactions for regular secondary alkylsubstituted amines and alcohols still remains a formidable challenge. In 2020, Zhou group reported a breakthrough in Ircatalyzed asymmetric hydrogenation of dialkyl ketones to afford chiral aliphatic alcohols with good enantioselectivity enabled by a rationally designed bulky PNP ligand 25 . Buchwald developed a seminal work on Cu-H-catalyzed hydroamination of internal alkenes to achieve chiral dialkyl amines 26,27 . In 2016, Fu group reported a pioneer work on Ni-H-catalyzed racemic hydrofunctionalizations of alkenes with aryl or alkyl halides 28 , which have become a promising alternative for traditional asymmetric C-C cross-coupling reaction to construct saturated stereogenic carbon centers [28][29][30][31][32][33][34][35] . The use of readily available and bench-stable alkenes as a masked nucleophile in the presence of silane circumvents the use of stoichiometric and often sensitive organometallic reagents, which usually require time-consuming preformation 36,37 . The abundance of alkene as well as the mild conditions significantly enhanced the scope and functional group tolerance of this strategy [38][39][40][41] . Fu group reported the seminal work on the anti-Markovnikov hydroalkylation of alkenes with activated secondary alkyl halides to build a stereogenic center originating from alkyl halides [42][43][44][45] . The use of unactivated alkyl halides to build stereogenic center originating from alkenes remains elusive due to the reversible Ni-H insertion onto alkenes and the propensity of chain-walking 46,47 . Recently, our group developed the Ni-H-catalyzed hydroalkylation of acrylates via anti-Markovnikov hydrometalation, giving the enantioenriched α-tertiary amides by forging a stereogenic center originating from acrylates 48 . In 2021, Hu group reported a hydroalkylation of vinyl boronates to give chiral secondary alkyl boronates enabled by the anchoring effect of boron 49 . These examples showcased the feasibility of building a stereogenic carbon center originating from alkenes via Ni-catalyzed hydroarylation [36][37][38] and hydroalkylation 48-51 of alkenes.
As part of our continuous interest in the enantioselective hydrofunctionalizations of alkenes, we envisioned the use of alkene adjacent to nitrogen or oxygen to undergo enantioselective hydroalkylation would furnish enantioenriched secondary aliphatic amine and alcohol derivatives (Fig. 1c). Here, we report the Ni-H-catalyzed regio-and enantioselective hydroalkylation of acyl enamines and enol esters with alkyl iodides to forge a stereogenic carbon center next to nitrogen or oxygen originating from alkenes in high enantioselectivity, providing a unified protocol for rapid access to chiral secondary alkyl-substituted amine and alcohol derivatives which are difficult to access otherwise [50][51][52] .

Results
Reaction optimization. To test the feasibility of the reaction, we set out to identify the reaction parameters using acyl enamine 1a with 1-iodo-3-phenylpropane 2a as substrate in the presence of silane. (Table 1 and Tables S1-13; for more details on the condition optimization, please see the Supplementary information). First, a wide range of chiral ligands were tested for this reaction using NiBr 2 .glyme (10 mol%) as the nickel catalyst precursor, trimethoxysilane (TMS) as hydride source, and potassium phosphate monohydrate as base in diethyl ether at room temperature (Table 1, entries 1-9 and Table S1). When pyridineoxazolidine ligand (L1 or L2) was used, the desired hydroalkylation product 3a was obtained in 54% and 29% yields with low Substrate scope of dialkyl amides. With the optimized conditions in hand, we turned to evaluate the scope of this reaction. First, we tested different alkyl iodides with tertiary acyl enamine 1a (Fig. 2). Then, 4-phenylbutyliodide was converted to chiral amide 3b in 93% yield with 92% ee. 2-Phenyl-1-iodoethane and α-branched alkyl iodides could be transformed into corresponding amine derivatives (3c and 3d) in 87% and 58% yields with 89% ee. Heterocyclic compounds, such as carbazoles, indoles, and thiophenes, worked well in the reaction, furnishing the regio-and  enantioselective hydroalkylation products (3e-3g) in 64-94% yields with 91% ee. Other functional groups, such as amides, esters, ethers were also compatible under the reaction conditions, delivering the desired chiral amine derivatives (3h-3k) in 56-83% yields with 89-92% ee. Moreover, silylethers and arylchlorides were tolerated in the reaction, giving the desired products (3l and 3m) in 85% and 95% yields with 74% and 88% ee, leaving chemical handles for further elaboration. Benzyl bromide was successfully converted to corresponding amide 3n in 88% yield with moderate enantiomeric excess. Second, internal acyl enamines were examined. Internal acyl enamines with diverse substituents could be converted to corresponding hydroalkylated products in good yields with excellent enantioselectivities. Acyl (E)-1-propenamine reacted to give corresponding dialkyl amide 3o in 74% yield with 90% ee. Alternatively, acyl (Z)-1-propenamine gave 3o in 80% yield with 81% ee under the same conditions. Longer alkyl chain-and benzyl-substituted internal acyl enamines were all good substrates for this reaction, affording corresponding amine derivatives (3p-3r) in 68-78% yields with 88-89% ee. Bromoindole containing alkyl iodide could be coupled with internal acyl enamine to deliver 3s in 63% yield with 92% ee.
Substrate scope of dialkyl esters. Next, enol esters were tested under the reaction conditions. To our delight, various enol esters could be tolerated and a wide range of chiral aliphatic alcohol derivatives were obtained in high enantioselectivity, which are difficult to access otherwise (Fig. 5). Aromatic or aliphatic acidderived enol esters were all good substrates for this reaction, furnishing corresponding chiral esters (6a-6c) in 53-73% yields with 80-92% ee. Alkyl iodides containing ester, ether, thiophene, amide could be transformed to corresponding chiral alcohol derivatives (6d-6g) in 51-80% yields with 90-95% ee. Notably, 1-iodohexane and 1-iodobutane were successfully involved in the reaction to give octan-2-ol (6h) and hexan-2-ol (6i) derivatives in 77% and 54% yields with 90% and 96% ee, respectively. Secondary alkyl iodide was tolerated in the reaction, furnishing the desired product (6j) in synthetic useful yields with 97% ee. Moreover, internal enol esters were well-tolerated in the reaction. Long-chain alkyl-substituted internal enol esters were successfully converted to corresponding chiral esters (6k-6m) in 58-70% yields with 91-94% ee. Chloro-containing alkyl-substituted internal enol ester underwent the desired hydroalkylation reaction to give 6n in 68% yield with 94% ee. The absolute configuration of the chiral ester was confirmed to be R by comparison to literature [53][54][55] . Furthermore, literature procedures proved unprotected chiral aliphatic amines and  Mechanistic consideration. Then, we carried out the reaction using deuterated silane (Ph 2 SiD 2 ) 32 under otherwise identical to standard conditions (Fig. 6). The reaction of terminal acyl enamine with 3-phenyl-1-iodopropane in the presence of Ph 2 SiD 2 afforded deuterated hydroalkylation product 7 in 61% yield with 93% ee (Fig. 6a). Only one deuterium incorporation (>95% D) was exclusively delivered to β-position to nitrogen of amide 7. No deuterium incorporation was found at α-position to nitrogen of 7. Next, the reactions of internal acyl enamine of both configurations were tested (Fig. 6b). The reaction of (E)-acyl enamine was slightly slower and delivered a lower yield and higher enantioselectivity of 9 in comparison to the generation of 8 from (Z)-acyl enamine 50,51 . These results indicated that Ni-H insertion onto acyl enamines to form alkyl-Ni species might be irreversible and enantio-determining.

Discussion
In summary, a unified protocol for Ni-catalyzed hydroalkylation of acyl enamines and enol esters with alkyl iodides under mild conditions was developed. The use of chiral BOX-based ligand enables the direct access of chiral secondary alkyl-substituted amine and alcohol derivatives in good yields with excellent levels of enantioselectivity, providing a straightforward alternative to pure aliphatic amine and alcohol derivatives which are traditionally challenging to access.

Methods
General procedure for hydroalkylation of tertiary acyl enamines. In a nitrogenfilled glovebox, Ni(COD) 2 (5.5 mg, 0.02 mmol, 10 mol%) and L9 (21.8 mg, 0.024 mmol, 12 mol%) were dissolved in solvent (2 mL, Et 2 O: DMF = 3:1) in a Schlenk tube with screw-cap equipped with a magnetic stirrer. The mixture was stirred at room temperature for 10 min, then alkyl halide (0.4 mmol), tertiary acyl enamine (0.2 mmol), and K 3 PO 4 ·H 2 O (0.6 mmol) were added sequentially. The mixture was cooled to 0°C before DMMS (74 μL, 0.6 mmol, 3 equiv.) was added dropwise. The resulting mixture was stirred at 0°C for 12-24 h (for 3o-s, stirred at 45°C). After completion of the reaction, the mixture was filtered through a pad of silica gel and washed with ethyl acetate (3 × 15 mL). The filtrate was washed with water (15 mL). The organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure, purified by flash chromatography with silica gel to give the pure product.  General procedure for hydroalkylation of secondary acyl enamines. In a nitrogen-filled glovebox, Ni(COD) 2 (5.5 mg, 0.02 mmol, 10 mol%) and L41 (8.4 mg, 0.024 mmol, 12 mol%) were dissolved in solvent (2 mL, Et 2 O: DMF = 3:1) in a Schlenk tube with screw-cap equipped with a magnetic stirrer. The mixture was stirred at room temperature for 10 min, then alkyl halide (0.4 mmol), acyl enamine (0.2 mmol), and K 3 PO 4 ·H 2 O (0.6 mmol) were added sequentially. The mixture was stirred at room temperature for another 5 min before DEMS (98 μL, 0.6 mmol, 3 equiv.) was added dropwise. The resulting mixture was stirred at room temperature for 12-24 h. After completion of the reaction, the mixture was filtered through a pad of silica gel and washed with ethyl acetate (3 × 15 mL). The filtrate was washed with water (15 mL). The organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure, purified by flash chromatography with silica gel to give the pure product.
General procedure for hydroalkylation of enol esters. In a nitrogen-filled glovebox, Ni(COD) 2 (5.5 mg, 0.02 mmol, 10 mol%) and L41 (8.4 mg, 0.024 mmol, 12 mol%) were dissolved in solvent (2 mL, Et 2 O: DMF = 3:1) in a Schlenk tube with screw-cap equipped with a magnetic stirrer. The mixture was stirred at room temperature for 10 min, then alkyl halide (0.4 mmol) was added and the mixture was stirred for another 5 min, followed by the sequential addition of enol esters (0.2 mmol) and K 3 PO 4 ·H 2 O (0.6 mmol). The mixture was stirred at room temperature for 5 min before DEMS (98 μL, 0.6 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16-20 h. After completion of the reaction, the mixture was filtered through a pad of silica gel and washed with ethyl acetate (3 × 15 mL). The filtrate was washed with water (15 mL). The organic phase was dried over Na 2 SO 4 , filtered, concentrated under reduced pressure, and purified by flash chromatography with silica gel to give the pure product.

Data availability
The authors declare that all other data supporting the findings of this study are available within the article and Supplementary information files, and also are available from the Ni(COD) 2 (10 mol%) L41 (12 mol%) K 3