Synthesis of α,β-unsaturated ketones through nickel-catalysed aldehyde-free hydroacylation of alkynes

α,β-Unsaturated ketones are common feedstocks for the synthesis of fine chemicals, pharmaceuticals, and natural products. Transition metal-catalysed hydroacylation reactions of alkynes using aldehydes have been recognised as an atom-economical route to access α,β-unsaturated ketones through chemoselective aldehydic C–H activation. However, the previously reported hydroacylation reactions using rhodium, cobalt, or ruthenium catalysts require chelating moiety-bearing aldehydes to prevent decarbonylation of acyl-metal-hydride complexes. Herein, we report a nickel-catalysed anti-Markovnikov selective coupling process to afford non-tethered E-enones from terminal alkynes and S-2-pyridyl thioesters in the presence of zinc metal as a reducing agent. Utilization of a readily available thioester as an acylating agent and water as a proton donor enables the mechanistically distinctive and aldehyde-free hydroacylation of terminal alkynes. This non-chelation-controlled approach features mild reaction conditions, high step economy, and excellent regio- and stereoselectivity.

Stabilization of an acyl-metal complex assisted by heteroatom chelation is a powerful strategy for obtaining E-enones. However, the installation and removal of the coordinating moieties entailed extra synthetic steps while reducing the step economy of the hydrofunctionalization. Though nondirected hydroacylation methods have been developed for alkenes or dienes [32][33][34][35][36] , to our knowledge, there is no general hydroacylation method for unactivated terminal alkynes that lead to chelating moiety-free Eenones. Mukaiyama, Weix, and Kishi independently reported that S-2-pyridyl (SPy) thioesters act as potential acyl donors for (cross-electrophile) coupling reactions [37][38][39][40] . We surmised that the thioester may act as both a transient SPy ligand and an acyl component [41][42][43][44] under nickel-catalyzed reductive coupling conditions to lead to acyl-Ni-SPy complex. A consecutive alkyne insertion and subsequent protodemetalation process may lead to hydroacylation product formation (Fig. 1c). However, the challenges of this anticipated reaction process to attain traceless alkyne hydroacylation are fourfold: (i) competition with nonconjunctive cross-electrophile (proton and thioester) coupling, (ii) reduction of substrates, (iii) iterative alkyne additions, and (iv) regio-and stereoselectivity issues. Therefore, precise reactivity and selectivity controls are crucial for a general approach to the hydroacylation of unactivated terminal alkynes. Herein, we report a nondirected and aldehyde-free approach to afford E-enones via a nickel-catalyzed reductive pathway.

Results and discussion
Optimization studies. To optimize the reaction conditions, S-(pyridin-2-yl) 4-methoxybenzothioate (1) and 3,3-dimethyl-1butyne (2) were chosen as model substrates, and a thorough screening of catalysts, reducing agents, additives, and solvents was conducted ( Table 1, see also the Supplementary Information (SI), Section III, Supplementary Tables 1-7). The standard conditions were established on the basis of inexpensive nickel(II) perchlorate hexahydrate, Zn, and ZnCl 2 in 1,2-DME to exclusively afford E-enone 3 in 81% isolated yield at room temperature (entry 1). The use of THF resulted in a similar yield (entry 2). Interestingly, coordinated water molecules were also found to be a suitable proton source (entries 3-5). The use of 17 mol% of Ni catalyst was appropriate for providing a stoichiometric 1 equiv of protons to the reaction. No desired product formation was observed in the absence of the nickel catalyst, Zn, or ZnCl 2 (entries 6-8). Mn as the reducing agent instead of Zn also appeared successful; however, this resulted in a diminished yield (entry 9). ZnCl 2 was found to be superior to MgCl 2 (entry 10). The complexation of thioester 1 by ZnCl 2 was examined by 1 H NMR spectroscopic studies (see the SI, Section VI). Using 1.5 equiv of terminal alkyne 2 was required for better conversion of the thioester (entry 11). The standard optimized reaction conditions were developed under an inert argon atmosphere; however, a significant amount of product formation was observed even under open atmosphere conditions (entry 12). Reduced reaction time or a decreased amount of Ni catalyst led to diminished yields (entries 13,14). In addition, the employment of acyl chloride or aldehyde as an acyl donor instead of thioester appeared to be completely unproductive (entries 15,16). Additional ligands in the hydroacylation resulted in slightly diminished yields for the substrates (entries 17, 18).
We then examined the scope of a wide range of alkynes. It is noteworthy that the reaction conditions b in Fig. 2 employ 2,2′dipyridyl disulfide (Py 2 S 2 ) to improve the reaction efficacy. The reduced SPy anion from Py 2 S 2 may provide an additional ligand source to stabilize nickel complexes (see also Fig. 1c). Acyclic-as well as cyclic aliphatic terminal alkynes, underwent the reaction to afford the corresponding vinyl ketones (33)(34)(35)(36)(37)(38) in moderate yields, although cyclopropyl-and cyclopentyl-derived alkynes gave the diminished yields. Aromatic alkynes bearing alkyl, phenyl, and phenoxy substituents worked well to give the desired products (39)(40)(41)(42)(43)(44)(45) with moderate to good yields. Ortho-, meta-, and para-substituted methoxy groups were also tolerated to obtain the products (46)(47)(48). Product 49 was isolated in 55% yield by using a disubstituted arylalkyne. Fluoro-and chloro-groups were examined and gave 50 and 51 in 63% and 56% yields, respectively. The strongly electron-withdrawing trifluoromethyl group led to product formation (52, 53) with diminished yields. 2-Ethylnyl-6-methoxy-naphthalene efficiently produced 54 in 76% yield. 2-Ethynylthiophene and 3-ethynylthiophene underwent the reaction smoothly to obtain the corresponding products (55, 56) in 39% and 58% yields, respectively. A free hydroxyl group was compatible affording 57 in 59% yield. We were delighted to find that the reaction was feasible with ethisterone, an agent for gynecological disease treatment, to afford 58 in 56% yield. The chemistry was also operative on a 1 mmol scale to give a similar yield. Symmetrical as well as unsymmetrical internal alkynes gave hydroacylation products (59-61) in low yields. The iterative reactivity yielding double-alkyne-insertion byproducts was observed (see also Fig. 3b). Activated alkenes also underwent the reaction smoothly to afford 62-64 in good yields.
Mechanistic investigations and deuterium labeling experiments. Control experiments were conducted to gain the insight into the reaction pathway. When the reaction was performed using Ni(COD) 2 as a catalyst, the desired hydroacylation product 3 was obtained in a 35% isolated yield. This study corroborates the oxidative addition of thioester 1 to zero-valent nickel species over the reaction course (Fig. 3a). The formation of hydroacylation product 60 suggests the protodemetalation of nucleophilic vinyl nickel complex I 45 . Interestingly, 65 and 66 were also isolated, verifying an iterative double-alkyne-insertion (Fig. 3b) and the presence of vinyl nickel species II [46][47][48] .
To identify the proton source of the hydroacylation, deuterium labeling tests were performed (Fig. 3c, see also Supplementary Figs. [6][7][8][9][10][11]. First, a reaction conducted using deuterium oxide (3.0 equiv) resulted in the formation of the product with 64 and 33% [D] incorporation at the βand α-positions, respectively, of unsaturated ketone [D]-3. π-Complexation of terminal alkynes to transition metal species gives its increased acidity 49,50 . Reversible H-D exchange between alkyne complex C (shown in Fig. 4) and D 2 O and subsequent migratory insertion lead to the incorporation of deuterium in the α-position of enone framework (see also the SI, Supplementary Fig. 12). Employing deuterated nickel(II) perchlorate hexahydrate also resulted in the deuterated enone [D]-3 (see also the SI, Section V). When we also performed the Proposed mechanism. Based on the above mechanistic studies and findings from previous reports [45][46][47][48]51,52 , we proposed a reaction pathway for this reductive hydroacylation as illustrated in Fig. 4. The reduction of Ni(II)(OH)X species E by zinc regenerates the active Ni(0) species A. Overall, readily available electrophiles (i.e., "H + " and "Ac + ") are incorporated into terminal alkynes in a reductive fashion 55 with excellent regio-and E-selectivity under mild conditions. This method can avoid the use of strong bases, organometallic reagents, and pre-installed chelating moieties.

Conclusions
In summary, we have demonstrated a nickel-catalyzed hydroacylation method of terminal alkynes to exclusively afford nontethered E-enones. S-(2-Pyridyl) thioesters not only serve as the acyl donor but also give the acyl-Ni(II)-SPy species as a key intermediate over the course of non-chelation-controlled catalytic events. It requires neither additional steps for removal of the coordinating group nor the use of a nucleophilic hydride source, further enhancing the efficacy of the method. We anticipate that these Ni-catalyzed reductive hydroacylation reactions will have an impact on synthesizing important synthetic intermediates, functional materials, and pharmaceuticals.

Data availability
Detailed experimental procedures, HRMS-ESI data and NMR spectra (PDF) for all compounds were provided in the Supplementary Information. Single-crystal X-ray data for 27 and 66 (CIF) are available free of charge from the Cambridge Crystallographic Database Centre (CCDC) under reference numbers 2039192 and 2036543.