Ni-catalyzed hydroaminoalkylation of alkynes with amines

Allylic amines are versatile building blocks in organic synthesis and exist in bioactive compounds, but their synthesis via hydroaminoalkylation of alkynes with amines has been a formidable challenge. Here, we report a late transition metal Ni-catalyzed hydroaminoalkylation of alkynes with N-sulfonyl amines, providing a series of allylic amines in up to 94% yield. Double ligands of N-heterocyclic carbene (IPr) and tricyclohexylphosphine (PCy3) effectively promote the reaction.

A llylic amines not only widely exist in a broad range of natural products and bioactive compounds, but also serve as versatile building blocks in organic synthesis [1][2][3][4] . The development of efficient and general methods for their synthesis has received much attention during the past several decades [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] . Among various reported methods, transition metal-catalyzed hydroaminoalkylation of π-unsaturated compounds, such as alkenes and alkynes represents one of the most straightforward and atom-economical synthetic routes [24][25][26][27][28][29][30][31] . With using either early [24][25][26] or late transition metals as catalysts [27][28][29][30][31] , a large number of hydroaminoalkylations of alkenes have been developed. However, in sharp contrast, analogous reactions of alkynes were faced with tremendous challenges (Fig. 1a), likely owing to difficult alkyne insertion and challenging protonolysis [32][33][34][35][36][37][38][39] . A pioneering investigation was conducted in 1989 by Buchwald and co-workers, who successfully obtained the allylic amine product by aqueous work-up. Despite an efficient protonolysis, the regeneration of Zr catalyst cannot be realized in this protocol, leading to stoichiometric Zr-complex needed 32 . Since then, much effort has been devoted to improving the reaction [33][34][35][36][37][38][39] , while the development of a catalytic method has been an elusive challenge. Most recently, during our submission, Schafer group used a tetradentate bis(ureate) ligand and metal Zr to in situ form a bulky Zr catalyst, achieving a catalytic hydroaminoalkylation of alkynes for the first time ( Fig. 1b) 40,41 . The bulky ligand proved critical to the reactivity, not only facilitating alkyne insertion, but also allowing the coordination of neutral amines to the metal center for subsequent easier protonolysis. Despite this big advance, the early transition metal Zr-catalyzed method still suffered from some undesired limitations such as unavoidable hydroamination side reaction in many cases, difficult-to-remove N-aryl protecting groups, and tricky regioselectivity under relatively harsh conditions. Therefore, the development of other efficient catalytic systems for hydroaminoalkylation of alkynes is still highly desirable. In this work, we use an inexpensive nickel as a catalyst to achieve a late transition metal-catalyzed hydroaminoalkylation of alkynes with N-sulfonyl amines, providing a series of allylic amines in up to 94% yield (Fig. 1c). The reaction features relatively mild conditions (80°C), general substrate scope of both amines and alkynes and high regioselectivity.

Results
Reaction optimization. In comparison with various hydroaminoalkylations of alkenes, the difficulty of hydroaminoalkylation of alkynes was ascribed to the following possible reasons: (1) strong basic and nucleophilic alkyl or aryl amines could coordinate to metal centers, resulting in either deactivation of transition metals or undesired side reactions such as hydroaminations; (2) weak acidity of N−H bonds cannot effectively undergo protonolysis of metallocycle intermediates. Thereby, the selection of proper N-protecting groups to increase the acidity of amines could be critical to the reaction efficiency, because more acidic amine would significantly reduce its coordination with metal centers and other side reactions such as hydroamination. However, to accommodate acidic N−H bonds, sensitive early transition metal complexes should be replaced by late transition metals such as Pd, Ru and Ni, because they could have better compatibility with protic substrates and solvents.
(TPS) was identified as the superior N-protecting group and Ni/ IPr/PCy 3 was identified as the optimal catalyst. With their combination, hydroaminoalkylation of alkyne 2a with N-TPS amine 1a smoothly proceeded under mild conditions (80°C), providing the corresponding allylic amine 3a in nearly quantitative yield (Fig. 2, entry 1).
Control experiments showed that the alteration of TPS resulted into significantly diminished yields (entries 2−8). For example, the replacement of isopropyl groups (TPS) by methyl groups (TMS) gave only 9% yield (entry 2). Common p-tolylsulfonyl (Ts) further decreased the yield to a trace amount (entry 3). The combination of NHC (IPr) and phosphine (PCy 3 ) ligands also proved critical to the reaction (entries 9−17). The absence of IPr·HCl completely inhibited the reaction (entry 9), whereas the reaction still gave 3a in 14% yield without the addition of PCy 3 (entry 13), demonstrating the vital role of IPr and the promoting effect of PCy 3 . In fact, a yield of 68% was detected with IPr alone at an elevated temperature (110°C) but with poor reproducibility (see the Supplementary Information for details). Other carbenes and phosphines were less effective (entries 10−12 and 14−17). Without Ni(cod) 2 or with other nickel species, the reaction did not work (entries 18−20).
Scope of amines and alkynes. Under the optimized conditions, various N-TPS amines were then examined (Fig. 3). Results showed that the reaction tolerated a broad range of functional groups on the phenyl ring of N-benzylamines, including simple alkyl (Me, 3b−3d), electron-donating groups (alkoxy, 3e and 3f), and electron-withdrawing groups (OCF 3 , F, Cl, CF 3 , CN, and CO 2 Me, 3g−3n), providing the corresponding allylic amines in 62−94% yields. In addition, the position of substituents did not have a strong influence on the reaction yield (3b−3d and 3h−3j). Notably, both 1-naphthyl (3o) and heteroaryl (3p) instead of the phenyl of 1a also worked well, affording both 86% yields. When the phenyl was replaced by the alkenyl, a decreased yield was obtained (45%, 3q) in the presence of 10 mol% of the catalyst at 110°C. Notably, various N-alkylamines were still compatible with the reaction (3r−3u, 41−54% yields), but requiring harsher conditions (130°C and 20 mol% catalyst) and a Ts protecting group. We reasoned that higher α-C-H bond strength of alkylamines than that of benzylamines and higher activation energy may result in this situation.
Next, a broad range of alkynes were investigated under the standard conditions (Fig. 4). Various diaryl alkynes bearing alkyls (4a−4e) and electron-donating groups (4f) on the phenyl rings were well compatible with the current reaction, providing the corresponding products in 79−92% yields. Notably, 2-tolylalkyne gave a 1:1 mixture of E:Z isomers (4c), probably because the significant steric hindrance on the aryl ring forced the alkene to isomerize.
Reaction utility and mechanistic investigation. To demonstrate the utility of the reaction, a gram-scale reaction of the model substrates was conducted under the standard conditions, affording the desired product 3a in 88% yield, without significant loss of the yield (Fig. 5a). In addition, the formed allylic amine 3a can act as a versatile synthetic intermediate to participate into various transformations. For example, hydrogenation followed by typical deprotection protocol of the sulfonyl group provided compound 5 in 68% yield. Moreover, direct oxidation of 3a resulted into a synthetically useful α-amino ketone 6 in 90% yield.
To gain insights into the reaction mechanism, some mechanistic experiments were carried out. Deuterium labeling experiments revealed that 100% allylic deuterium and 94% olefinic deuterium existed in product d−3a, together with deuterated Zstilbene (12% yield). This result showed that there was partial deuterium-scrambling at the vinylic position, which may be ascribed to a reversible insertion of C=C double bonds in products or stilbene into N−H bonds (Fig. 5b). In addition, deuterated Z-stilbene was obtained, indicating that a part of alkynes were reduced during the reaction process. Crossover experiments between d−1a and 1e suggested that the allylic and olefinic hydrogens may originate from different amide molecules (Fig. 5c), excluding an oxidative addition pathway. The observed kinetic isotopic effect (k H /k D = 2.7 in the intermolecular competitive reaction and k H /k D = 2.2 in parallel reactions, Fig. 5d) implied that the cleavage of the benzylic C−H bond could be involved in the rate-determining step. Notably, in case of dimethylamino benzylic amide 1v as the substrate, imine 1v′ was detected (Fig. 5e). Moreover, the competitive reaction between amide and the imine showed that both of them gave the corresponding products in comparable yields (see Supplementary Information).
These results suggested that an imine intermediate could be involved in the catalytic cycle. In addition, the stoichiometric reaction of a five-membered nickelacycle [42][43][44] and amide 1a with or without IPr afforded the desired product 3b in 68% and 9% yields, respectively, suggesting that both the nickelacycle and IPr were critical to the reaction (Fig. 5f). Based on these mechanistic experiments and previous literature reports [45][46][47][48][49] , a possible reaction mechanism was proposed ( Fig. 6). At the induction stage, the nickel-catalyzed transfer hydrogenation of alkyne 2a with amine 1a furnishes Z-stilbene and imine 1a′. Then, 1a′, 2a,  activation Gibbs energy of 24.8 kcal/mol, which is in accordance with the observed kinetic isotopic effect (Fig. 5d). Finally, ligand exchange between IN10 and 2a takes place, releasing the final product and IN5, which triggers the next catalytic cycle. DFT calculations with TPS-protected substrate 1a and IPr ligand indicated that the overall activation Gibbs energy is 22.4 kcal/mol. Replacement of TPS by Ts leads to a higher overall activation Gibbs energy of 24.9 kcal/mol. These results suggested that, as compared with the Ts group, a ca. 30fold acceleration effect of the TPS group would be expected at 80°C, which nicely reproduced the experimentally observed superior performance of the TPS protecting group (Fig. 2, entry 1 vs. entry  3). In addition, DFT calculations also suggested that the presence of PCy 3 may not reduce the overall activation Gibbs energy of the Nicatalyzed reaction since replacement of NHC by PCy 3 did not promote the turnover-limiting hydrogen transfer step (see Supplementary Fig. 8). Instead, PCy 3 may act as an auxiliary ligand to facilitate the generation of the catalytic species and/or to inhibit catalyst deactivation.

Methods
General procedure for hydroaminoalkylation. To a 15 mL pressure tube were added Ni(cod) 2 (2.75 mg, 0.01 mmol), IPr·HCl (4.25 mg, 0.01 mmol), PCy 3 (2.8 mg, 0.01 mmol), KO t Bu (1.34 mg, 0.012 mmol), toluene (2.0 mL), alkynes (0.22 mmol) and amines (0.20 mmol) in a glove box. The tube was sealed with a Teflon cap and the mixture was stirred at 80 or 110°C for 1-12 h. After cooled to room temperature, the crude product was filtered through a short pad of Celite, and the filtrate was concentrated under vacuum. The resulting residue was obtained by chromatography on silica gel column with petroleum ether/ethyl acetate as the eluent.

Data availability
The authors declare that the data supporting the findings of this study are available within the article and its Supplementary Information file.