Temperature-Regulated Regiodivergent Synthesis via Alkene Migratory Hydroalkylation

An approach for reliable and predictable carbon-carbon or carbon-heteroatom bond formation that produces either regioisomer starting from the same raw materials, also known as a regiodivergent methodology, is highly desirable. Altering the chemical reaction variables, including catalysts, ligands, solvents, or other additives, were the predominant strategy for the implementation of regiodivergent features in metal-catalysed organic synthesis. The achievement of switchable selectivity using quickly and conveniently controlled physical variables constitutes a desirable goal with an intriguing method of attainment. Herein, we report our discovery that temperature-regulated switchable site-selectivity can be achieved in alkene (migratory) functionalization. Judicious selection of reaction temperatures, one of the most easily changed variables, led to protocols that provide the regiodivergent alkylation products starting from a single alkene substrate. This protocol allows for the convenient synthesis of α- and β-branched protected amines, both of which are substantially important to the pharmaceutical chemistry and biochemistry fields. In addition, enantioenriched β-branched alkyl amines could be accessed in a catalytic asymmetric variant manner. This work may inspire more research interests in metal-catalysed regiodivergent reaction discovery using easily changed physical variables.


Introduction
Reliable and predictable catalytic reactions that produce either regioisomer when starting from the same raw materials, also called regiodivergent reaction methodologies, are highly desirable. The different regioisomers can be prepared by properly interchanging the catalysts or altering the reaction conditions. 1,2 Therefore, these regiodivergent reactions exhibit higher productivity, better atom-and step-economy, and better cost-efficiency and are quickly gaining favour in synthetic organic chemistry. As was summarized by Nájera and coworkers, different catalysts, ligands, solvents, or additives, were the predominant strategy for the implementation of regiodivergent features in metal-catalysed organic synthesis. 1 The achievement of switchable selectivity using quickly and conveniently controlled physical variables constitutes a desirable goal with an intriguing method of attainment. Reaction temperature, one of the most easily changed physical variables in organic synthesis, can affect the regioselectivity of reactions (Figure 1a). For example, the Kolbe-Schmitt reaction, the named reaction for the synthesis of salicylic acid, is a thermodynamically controlled equilibrium reaction. A lower reaction temperature is conducive to the formation of ortho-isomers, and a higher reaction temperature is conducive to the formation of para-isomers. Fries rearrangement reaction also exhibits a temperature-regulated regiodivergence. In another example, Martin and coworkers reported the discovery of a temperature-dependent regiodivergent remote carboxylation of alkyl halides with carbon dioxide. 3 The site-specific formation of carbon-carbon or carbon-heteroatom bonds provides new insight to chemists during retrosynthetic analysis. [4][5][6] Alkene (migratory) functionalization represents an attractive method for the construction of carbon-carbon bonds and carbon-heteroatom bonds. [7][8][9][10][11][12] The in situ generation of alkyl-metallic intermediates from widely accessible alkenes circumvents the time-consuming use of reactive and often sensitive organometallic reagents in traditional electrophile-nucleophile cross-coupling, which improves our everexpanding synthetic toolkit for forming sp 3 hybridized linkages. [13][14][15][16][17] In addition, carbon-carbon bond formation on remote and unfunctionalized sites enabled by the chain-walking process, a formal translocation of the original active site to a nonspecific position along with the carbon skeletons, allows for the synthesis of complex structures that would otherwise be difficult to prepare. [18][19][20][21][22][23][24][25] In the context of alkene functionalization, both catalysts and ligands could regulate the regiodivergence of hydrofunctionalization [26][27][28][29] and difunctionalization process [30][31][32][33][34] . In consideration of the essential problem that to achieve switchable selectivity using easily changed and controlled physical variables, switching reaction temperatures to provide the regiodivergent products starting from a single alkene substrate would be an ideal choice.
Inspired by these achievements, we sought to explore the influence of temperature on accurate and switchable site selectivity in alkene functionalization reactions. Herein, we report our discovery that switchable selectivity can be achieved in nickel-hydride-catalysed alkene migratory hydroalkylation (Figure 1c). Judicious selection of reaction temperatures led to protocols that provide the regiodivergent α-and β-C-H alkylation products and start from a single alkene substrate. This reaction also exhibits regioconvergence, delivering the predictable regioselective product with high regioselectivity from the arbitrary isomer or even isomeric mixtures of the alkene substrates. This protocol allows for the convenient synthesis of α-and β-branched alkyl amines, each of which are substantially important to the pharmaceutical chemistry and biochemistry fields. Furthermore, enantioenriched β-branched alkyl amines could be accessed in a catalytic asymmetric variant manner, which provides a convenient synthetic route to enantioenriched β-branched alkyl amines that are substantially important to the pharmaceutical chemistry and biochemistry fields (Figure 1d). 35 Figure 1. Regiodivergent alkene functionalization and our stratergy: temperature-regulated regiodivergent and regioconvergent alkene migratory hydroalkylation. T.M., transition-metal; Ac, acetyl; Piv, pivaloyl; Boc, tbutoxycarbonyl.

Results
Reaction discovery and optimization. The widespread nature of C(sp 3 )-C(sp 3 ) structures makes it essential for organic synthetic chemists to improve the construction of these common bonds. 36 The developments in pharmaceutical chemistry also create a need for new synthetic methods that facilitate alkyl carbon centres. [4][5][6] The utilization of regiodivergent alkene hydroalkylation to access the C(sp 3 )-C(sp 3 ) bond was highly desired.
We systematically screened all reaction parameters and determined that a combination of NiBr2 (diglyme) and bisoxazoline ligand L with (EtO)3SiH and K3PO4 (H2O) in DMAc at 10 °C was critical for success, and an 86% GC yield and a 12:1 r.r. were obtained. More detailed information on the changes of each reaction parameter is summarized in Figure 2a. Careful selection of the bisoxazoline ligand played an extremely vital role in the success of this reaction. The structurally related bipyridine (L1 and L2), bioxazoline (L3), and pyridine-oxazoline (L4) ligands were tested and gave moderate to good yields with poor regioselectivities (1:3.6~1.7:1 r.r.). A small amount of the target product was observed when we used a diamine ligand (L5). Many other nickel catalysts could be used, such as NiBr2 and NiI2 (entry 2), but Ni(acac)2 was invalid for this reaction (entry 3). Many other oxygenbearing silanes, such as DEMS, PMHS and (MeO)3SiH, could be used instead of (EtO)3SiH with slightly decreased coupling efficiency and comparable regioselectivity (entry 4). Ph2SiH2 delivered a gratifying 8.1:1 regioisomeric ratio with a low 22% total yield (entry 5), while the less electrophilic hydrosilane Et3SiH provided no cross-coupling product (entry 6). K3PO4 without crystal water also performed well (entry 7); Na2CO3 provided excellent regioselectivity, but the coupling yield was unsatisfactory (entry 8); lower yields and poor regioselectivities were obtained using a medium strength base such as KF or CsF (entry 9). Various solvents were compared to the optimal solvent DMAc. Amide solvent, DMF, afforded a high regioisomeric ratio with a slightly decreased 75% yield (entry 10). Polar aprotic CH3CN, ether THF, and hydrocarbon solvents such as toluene and DCE were inferior and exhibited significantly reduced regioselectivities (entry 11). Finally, this hydroalkylation reaction could not be performed without nickel catalysts (entry 12); a halved yield of 42% with a roughly equal 11:1 regioisomeric ratio was obtained in the absence of the bisoxazoline ligand L (entry 13).
With respect to migratory α-selective hydroalkylation, we found that the increased reaction temperature led to a reversed α-selectivity that allowed for the production of 4aa with both high regioselectivity and an excellent coupling yield (Figure 2b). A good GC yield of 97% and a 94% isolated yield with a superb regioselectivity profile (>20:1 r.r.) resulted under similar reaction conditions for the migratory β-selective hydroalkylation shown in Figure 2a, and only the modification was the increase in reaction temperature to 100 °C. Therefore, judicious selection of reaction temperatures, one of the most easily changed variables in organic synthesis, led to protocols that provide the regiodivergent α-and β-C-H alkylation products starting from a single alkene substrate.
Finally, we determined that enantioselective β-selective hydroalkylation could be realized (Figure 2c). With slight modifications to the solvent and reaction temperature based on the reaction conditions for migratory βselective hydroalkylation, the protected allylamine 3a and alkyl iodide 2a coupled well to deliver the enantioenriched β-branched amine 6aa with a 96% GC yield, an 89% isolated yield and a good regio-and enantioselectivity profile (9.2:1 r.r. and 94% e.e.). The mixed DMF/ t BuOH solvent exhibited a slight advantage over the single solvents, such as DMAc, DMF, or THF, with regard to both regio-and enantioselectivity (entries 2~4). MeOH was inferior because its use resulted in low alkene conversion (entry 5). A slightly increased reaction temperature at 21 °C rather than 10 °C improved the yield (entry 6). Comparative results on other bisoxazoline ligands are also listed (see Supplementary Table 3 for more details). More benzyl substitutions on the linkage of bisoxazoline improved the yield and enantioselectivity (L* versus L6 versus L7). Aryl substitution on the oxazoline ring performed better than other substitutions, even structurally similar indan substituents (L* versus L8). a Yield refers to the total yield for the mixture of all regioisomers. b r.r. refers to the regioisomeric ratio of the major product to the sum of all other isomers. For alkene migratory hydroalkylation and enantioselective hydroalkylation, α-, β-and linear-selective products were observed; other regioisomers could hardly be detected.
Yields and regioisomeric ratios were determined by GC analysis with triphenylmethane as an internal standard. Substrate scope of migratory hydroalkylation. We sought to examine the generality of this migratory hydroalkylation reaction with suitable reaction conditions by exploring a wide range of alkenes and alkyl iodides ( Figure 3). An array of alkene substrates with different steric hindrances and chain lengths smoothly underwent alkene isomerization hydroalkylation, convincingly demonstrating the reliability of temperature-regulated regioselectivity. The regioselectivity was precisely controlled by the reaction temperature: high temperature (100 °C) was always α-selective, whereas low temperature (10 °C) was β-selective. In addition, a complete lack of isomerization of the alkyl halides was observed. Both terminal aliphatic alkenes (4aa and 5aa, 4ca and 5ca) and internal alkenes (4ba and 5ba) with different chain lengths performed well. Alkane substrates 1d and 1e have potentially competitive benzylic or α-ester active reaction sites. These substrates delivered prospective α-or βselective migratory hydroalkylation products (4da and 5da, 4ea and 5ea, respectively), indicating that the amide group displays a higher priority directing ability over an aromatic ring or an ester group. However, α-selective migratory hydroalkylation exhibits better regiocontrol capability and applies to a broader range of alkene substrates than β-selective migratory hydroalkylation. Both method A and method B were performed on the 1,1disubstituted alkene 1f. α-Branched product 4fa was obtained smoothly under method A conditions, while method B produced the unexpected linear product 5fa (see Supplementary Figure 26 for DFT calculation results).
A variety of alkyl iodides with various functional groups were readily converted to the target products in moderate to good yields (52~91%) and with high regioisomeric ratios (5.2:1~>20:1 r.r.). We successfully transformed the alkyl iodides 2b and 2c to a series of products (4ab and 5ab, 4ac and 5ac), which indicates that the regiodivergence of the reaction does not rely on alkyl halide substrates bearing specific heteroatoms. Many valuable synthetic functional groups including esters (4ad and 5ad), trifluoromethyls (4ae and 5ae), and various heterocyclic groups such as thiophene (4af and 5af) and furan (4ag and 5ag) were compatible with the use of mild and robust reaction conditions. This reaction is highly chemoselective to electrophilic aryl chloride (4ah and 5ah), aryl tosylate (4ai and 5ai), and nucleophilic arylboronate (4aj and 5aj), thus allowing further transformation through other cross-coupling reactions. to be suitable substrates. Excellent enantioselectivities (88~96% e.e.) were obtained in all cases. In general, alkenes with less bulky substituents provided good yields (6ba, 6da), while bulkier substrates resulted in moderate coupling efficiency (6cJ). Notably, the Z/E configuration of the alkene indeed affects the regio-and enantioselectivity (6da). Another limitation of this reaction is that the regioselectivity of the reaction is not satisfying when utilizing substrates with intolerable ester groups in the alkyl chain (6ea, 6fa), which suggests that there is a need to further optimize the reaction conditions. Cinnamylamine derivatives have potentially competitive benzylic active reaction sites. We examined several cinnamylamine derivatives with different electronic properties of the aryl ring. Both electroneutral (6gb), electron-rich (6hb, 6ia), and electron-deficient (6ja, 6ka) compounds gave uniformly good coupling yields and regio-and enantioselectivities.
Finally, the absolute configuration of 6aJ was determined by comparison with that of the standard product (see Supplementary Note 2 for more details). We assigned the corresponding absolute configuration to other products.   (Figure 5a). Derivatives of indomethacin (2w), coumarin (2x), and probenecid (2y) were smoothly reacted with alkene 3a to provide the desired products (6aw, 6ax, and 6ay) in good yield (72~89%) and selectivity (93~96% e.e. and 7.9:1~11:1 r.r.). In the modification of natural products L-proline (2v), estrone (2z), and D-galactopyranoside (2A), we obtained diastereoisomers (6av and 7av, 6az and 7az, 6aA and 7aA) using the proper enantiomer of the ligand. The preloaded chiral centres in the natural products hardly affect the coupling efficiency and regio-and enantioselectivity of the reaction. In terms of scalability, the synthesis of product 6aB could be conducted on a gram scale with an 86% yield (Figure 5b). After hydrolysis of 6aB with HCl in propanol, deprotected primary alkyl amine 8 was obtained in a 70% isolated yield. Reduction of 6aB by LiAlH4 afforded the corresponding secondary amine 9 in a 90% isolated yield. The scale-up reaction and easy removal of the protecting group highlight the practicality of this β-branched alkyl amine synthesis. We applied this reaction to synthesize intermediates of bioactive molecules and their analogues (Figure 5c). Compound 6lC was prepared as the intermediate of the acesodyne medication Lyrica, a γ-aminobutyric acid (GABA) receptor agonist.
We also synthesized an elongated analogue (6gD) of amphetamine (a synthetic stimulant-type medication) and a structural analogue (10 and 11) of coniine (a polyketide-derived alkaloid) in short synthesis steps. We further demonstrated the utility of this temperature-regulated migratory hydroalkylation by employing isomeric mixtures of alkenes (Figure 5d). Our protocol exhibited both regiodivergence and regioconvergence, delivering each predictable regioselective product 4ba or 5ba with high regioselectivity from isomeric mixtures of the alkene substrates.
A series of conventional deuterium labelling experiments further improved our understanding of the detailed reaction mechanism. The migratory hydroalkylation of the alkene 1a was conducted under both method A and method B using Ph2SiD2 (Figure 6b). We observed the incorporation of deuterium at the γ and δ positions of the amide group, and no H/D exchange was observed at the α or β position of the amide group. The deuterium content at the δ position is always higher than that at the γ position, indicating that Markovnikov-(rather than anti-Markovnikov-) hydrometallation is favoured. No α-or β-deuterium atom was observed, thus excluding the possibility of nickel walking back and forth along the alkyl chain. Furthermore, β-located alkyl-nickel could participate in cross-coupling or migrate to the α position but could not migrate to the outer γ-position. A δ,δdideuterated alkene (δ,δ-d2-1a) was reacted with the alkyl halide 2a under method A and method B separately ( Figure 6c). It is interesting to note that the deuterium content at the δ-position decreased slightly, and no H/D exchange was observed along the chain. This phenomenon indicated that the γ-located nickel prefers chain walking toward the amide group to from α-or β-located alkyl-nickel species. A β,β-dideuterated alkene (β,β-d2-1a) was reacted with alkyl halides 2k and 2H (Figure 6d). The β-and γ-position deuterated products d2-4ak and d2-5aH were obtained, respectively, and no deuteration was observed at the α position of the amide group. This conclusion was similar to that obtained from Figure 6c; nickel walking back and forth along the alkyl chain was less likely; in particular, α-located alkyl-nickel could not migrate to the outer β-or γ-position. We studied the stereochemistry of the asymmetric catalytic process using Ph2SiD2 to conduct deuterium-labelling experiments (Figure 6e). Under method C, 3a smoothly reacted with 2k to deliver the deuterated product d1-6ak using Ph2SiD2. Deuterium was incorporated exclusively at the γ-position of the amide substituent. Thus, in this case, anti-Markovnikov-hydrometallation was completely forbidden. We observed a highly matched Z/E ratio of the starting material alkene (3g) and diastereoselectivity of products (6gI and 6gI') using either optically pure ligand or racemic ligand. We suggested that irreversible syn-hydrometalation was the regio-and enantio-determining step. In total, we could conclude that nickel chain walking was not in a back-and-forth modality but in a unidirectional modality, i.e., toward the amide group and to form the α-or β-located alkyl-nickel species.  Method A was carried out at 55 °C for a better balance between reasonable regioselectivity and reaction rate.

Catalyst characterization and reaction kinetics.
More information about the asymmetric catalytic process was obtained through catalyst characterization and reaction progress kinetic analysis. The enantiopurities of the ligands used and the obtained hydroalkylation products exhibited a linear relationship (Figure 7a). Therefore, a monomeric nickel complex and a single bisoxazoline ligand were involved in alkene hydrometalation as the enantio-determining step. In addition, the enantiomeric excess of the desired product would not be expected to change during the reaction process (Figure 7b). Reaction progress kinetic analysis (RPKA) of the model reaction   Figure 8a, and the catalytic cycle for the proposed mechanism is shown in Figure 8b. The Ni(I) complex (IN1 in Figure 8a, A in Figure 8b) was suggested to be the initial catalyst under reductive conditions, generated by Ni(II)→Ni(0) reductive elimination and the comproportionation of Ni (II) and Ni(0) species. 15 Ni(I)X (A) reacted with an alkyl halide (2) to afford Ni(II)X2 (IN2 in Figure 8a, B in Figure   8b) and the corresponding alkyl radical (2') through halogen-atom abstraction. Ni(II)X2 (B) reacted with hydrosilane to deliver a Ni(II)H complex (IN3 in Figure 8a, C in Figure 8b reductive elimination to deliver the α-selective hydroalkylation product (4) and regenerate the Ni(I)X catalyst (A). The driving force for migratory α-selective hydroalkylation was the relatively lower (by 1.7 kcal/mol) energy barrier for reductive elimination from IN12 compared to that of IN8 (β-selective). The rate-determining step for α-selective hydroalkylation was the β-hydride elimination step (IN8→TS7). The sudden energy decrease of TS7 →IN10→TS8→IN11 made it an irreversible step. This result was consistent with the outcomes in Figure 6d that α-located alkyl-nickel could not migrate to the outer β-or γ-position. In total, the thermodynamic stability of IN12 over IN8 was responsible for the α-selective hydroalkylation, while the kinetics advantage of IN8→TS6 over IN8→TS7 was responsible for the β-selective hydroalkylation. In addition, the computational results reasonably explained our conclusion in Figure 6b~d that the chain walking of nickel was not in a back-and-forth modality but in a unidirectional modality, i.e., toward the amide group and to form the α-or β-located alkyl-nickel species.
Notably, we also proposed a Ni ( According to our deuterium labelling experiments shown in Figure 6e, the enantio-determining step was revealed as the hydrometallation step, i.e., the migratory insertion of Ni(II)H to produce IN7 (E). A comparison of TS5-S and TS5-R was conducted and is shown in Figure 8c. TS5-S was thermodynamically disfavoured, which could be attributed to the repulsion between the aryl substituent group in the ligand and the alkyl group in the amide protecting group. It can also be seen from the quadrant diagram obtained perpendicular to the Ni-ligand direction that the ligands are mainly distributed in quadrants II and IV. For TS5-S, the alkyl chain has steric repulsion with the ligand in quadrant IV, making it relatively unstable. The feasibility of TS5-R resulted in the major S-configuration products.

Conclusions
We disclose a temperature-regulated regiodivergent route for C(sp 3 )-C(sp 3 ) bond formation, a scarce phenomenon in transition-metal-catalysed organic synthesis. Regiodivergent alkylation was realized by varying only the reaction temperatures of alkene migratory hydroalkylation starting from the same raw materials, the identical alkene and alkyl halide substrates, using the same nickel-hydride catalytic system. This reaction also exhibits regioconvergence, delivering the predictable regioselective product with high regioselectivity from the arbitrary isomer or even isomeric mixtures of the alkene substrates. This protocol allows for the convenient synthesis of α-and β-branched alkyl amines, each of which are substantially important to the pharmaceutical chemistry and biochemistry fields. Detailed mechanistic studies revealed that, the formation of more stable nickelacycle provides the strong driving force of directional migration and the thermodynamic and kinetic properties of different reduction elimination intermediates are responsible for the switchable site-selectivity.
Thermodynamic stability of the corresponding reduction elimination intermediate is responsible for the αselective hydroalkylation, and kinetics advantage is crucial for the β-selective hydroalkylation. This research work confirms the opportunity and possibility that reaction temperature, one of the most easily changed physical variables in organic synthesis, can serve as a determining parameter in alkene (migratory) functionalization. We believe that temperature-regulated regiodivergent mode might be generalizable in metal-catalysed alkene functionalization, providing quick and convenient synthetic routes to diversified molecules.

Methods
General procedure for temperature-regulated migratory hydroalkylation. In the air, a 10 mL screw-cap test tube equipped with a magnetic stirrer was charged with NiBr2(diglyme) (0.02 mmol, 10 mol%), L (0.03 mmol, 15 mol%) and tri-potassium phosphate monohydrate (0.6 mmol, 3.0 eq.). The test tube was evacuated and backfilled with argon for three times, then DMAc (1.2 mL) was added. After the reaction solution was cooled to 0 °C, (EtO)3SiH (0.6 mmol, 3.0 eq.) was added dropwise via syringe, then the reaction solution was kept stirring for 15 min at 40 °C until the system color turns dark brown. Next, alkyl halide (0.4 mmol, 2.0 eq.) and alkene (0.2 mmol, 1.0 eq.) were added after the resulting solution was stirred for 2 min at 0 °C, then the solution was stirred at 100 °C or 10 °C for 12 h. The reaction mixture was diluted with H2O followed by extraction with EtOAc, dried with anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give the target product.
General procedure for enantioselective β-selective hydroalkylation. In the air, a 10 mL screw-cap test tube equipped with a magnetic stirrer was charged with NiBr2(diglyme) (0.02 mmol, 10 mol%), (S,S)-L * (0.03 mmol, 15 mol%) and tri-potassium phosphate monohydrate (0.6 mmol, 3.0 eq.). The test tube was evacuated and backfilled with argon for three times, then solvent (DMF: t BuOH = 1:1, 1.2 mL) was added. After the reaction solution was cooled to 0 °C, alkyl halide (0.4 mmol, 2.0 eq.) and alkene (0.2 mmol, 1.0 eq.) were added. Next, (EtO)3SiH (0.6 mmol, 3.0 eq.) was added dropwise via syringe, the reaction solution was kept stirring for 5 min at 0 °C, then the solution was stirred at 21 °C for 12 h. The reaction mixture was diluted with H2O followed by extraction with EtOAc, dried with anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give the target product.

Data availability
The authors declare that the data supporting the findings of this study are available within the article and Supplementary Information files or from the corresponding author upon reasonable request. The experimental procedures, computational results and characterization of all new compounds are provided in the Supplementary Information.