Copper-Catalyzed Diboron-Mediated cis-Semi-Hydrogenation of Alkynes under Facile Conditions

Cis-alkenes are ubiquitous in biological molecules, which makes it greatly significant to develop efficient methods toward construction of cis-olefins. Herein, we reported a facile semi-hydrogenation of alkynes to cis-alkenes in an efficient way with cuprous bromide/tributylphosphine as the catalyst and bis(pinacolato)diboron/methanol as the hydrogen donor. The method features convenient and facile reaction conditions, wide substrate scope, high yields, and high stereoselectivity.


Introduction
The cis-alkene functionality is widely occurring in pharmaceuticals, fine chemicals, pesticides, and natural products [1][2][3][4][5][6]. For example, cis-combretastatin A4, a stilbene derivative from Combretum caffrum, is considered to be a strong cell growth and tubulin inhibitor [7]; cis-asarone, derived from Acorus gramineus, has antifungal activity [8]; cruentaren A, a cytotoxic natural product isolated from myxobacterium Byssovorax cruenta, exhibits selective inhibition of F-ATPases, thus showing cytotoxicity against a variety of cancer cell lines [9,10]; chavicine, a cis-alkene, is proven to be the precursor compound for the neuroprotective effects of black pepper [11]; haliclonacyclamine F, a bis-piperidine alkaloid, has been isolated from the marine sponge Pachychalina alcaloidifera [12] (Figure 1). Therefore, methods for the construction of double bonds with high stereoselectivity have long attracted the interest of the synthetic community, and several related approaches have been developed, such as Wittig reaction [13], Horner-Emmons-Wadsworth reaction [14], Julia-Kocienski reaction [15], Peterson reaction [16], Takai olefination [17], olefin metathesis [18], cross-coupling reaction [19], alkyne semi-hydrogenation [20], halide elimination [21], and so on. Among these methods for the selective construction of double bonds, alkyne semihydrogenation is an attractive route due to its simplicity, atomic economy, and highly controllable stereoselectivity [22][23][24]. Semi-hydrogenation of alkynes by Pb(OAc) 2 -modified Pd/CaCO 3 , Diboron reagents, which are highly stable and easy to handle, have served as common borylation reagents and are widely used in transition-metal catalyzed borylation reactions [51,52]. Meanwhile, the exploitation of the intrinsically reducing B-B bond has attracted considerable attention due to its obvious advantages in terms of safety and green chemistry compared to the commonly used silanes [53][54][55]. For example, in 2016, Stokes' group published the transfer hydrogenation of carbon-carbon double bonds catalyzed by Pd/C with B 2 (OH) 4 /water as the reductant in dichloromethane [56]. In 2019, Liu's group discovered a method for selective transfer of hydrogen from ethanol to alkynes with the assistance of NHC ligands and t BuOK (Figure 2c) [57]. In the same year, Shi's group developed a similar method for the cis-selective semi-deuteration of alkynes, with the difference that expensive xantphos and LiO t Bu were used to facilitate the reaction (Figure 2c) [58]. Although these copper-catalyzed semi-hydrogenation of alkynes have made remarkable developments, all of them must use structurally complex and expensive catalytic systems, thus simple and facile reaction systems for this process still require further exploration. Based on the continued exploration of the properties of diboron reagents in our group [59][60][61][62], we herein report a copper-catalyzed alkyne semi-hydrogenation based on B 2 pin 2 -mediated transfer hydrogenation, which requires only simple and cheap n Bu 3 P and NaOH while good stereoselectivity is highly maintained.

Results and Discussions
To explore the optimal reaction conditions, diphenylacetylene was chosen as the standard substrate. Through screening of copper catalysts, CuBr was found to be the best catalyst for this semi-hydrogenation (entries 1-4, Table 1). The absence of ligands or addition of other phosphine ligands resulted in lower yields (entries 5-8, Table 1). Poor yields were obtained when B 2 (OH) 4 was used instead of B 2 pin 2 (entry 9). Other bases, including LiO t Bu (entry 10), weak bases (entry 11), and strong organic bases (entry 12), were not as effective as NaOH. Screening of the solvents showed that DMF as solvent provided the best reaction results (entries 13-17, Table 1). Unfortunately, a lower reaction temperature resulted in a decrease in the yield and stereoselectivity (entries 18-19, Table 1). Then, control experiments were conducted which demonstrated that both the copper catalyst and B 2 pin 2 were indispensable for the reaction (entries 20 and 21). Based on the above screening results, we chose the reaction conditions in entry 1 as the optimal conditions. Following the optimization of the reaction, a series of alkynes were tested to demonstrate the scope of the reaction (Scheme 1). For different internal alkynes, the target products (2a-b, 2f-l) were obtained in moderate to excellent yields as well as good to excellent stereoselectivity, regardless of the electron-withdrawing or electron-donating group, particularly, the readily reduced carbonyl (2j) and cyano groups (2k) were compatible with these reaction conditions. Different substitution patterns, including ortho-, meta-, paraand multisubstitution, had slight effect on the efficiency and selectivity of the reaction (2c-e). The 1-naphthyl-containing substrate gave 2m in moderate yields, however, with excellent stereoselectivity, which may be attributed to the steric hindrance of the 1-naphthyl group. For the substrate 1n containing 2-thienyl group, excellent yield and stereoselectivity were obtained. This strategy was also applicable to monoalkyl or dialkyl substituted alkynes (2o-t) with good to high stereoselectivity, but lower yields resulted for the bulky alkynes. To our delight, the unprotected hydroxyl group did not cause negative effects on the reaction (2p and 2r). Under the above reaction conditions, the semi-hydrogenation products could also be obtained from terminal alkynes (2u-w). The occasionally lower stereoselectivities observed in the cases of 2c, 2d, 2f, and 2q have not been reasonably explained yet since the stereoselectivity is the result of combination effects of steric hindrance and electronic effects of functional groups, making it difficult to predict which factor predominates (see SI for a possible isomerization mechanism which involves a reversible addition-elimination process). The Z/E ratios were determined by 1 H NMR. c Reaction was processed with CuBr (0.2 equiv), n Bu 3 P (0.4 equiv) under 60 • C.

Mechanistic Study
Control experiments were performed to gain further insight into the reaction mechanism. First, isotope labeling experiments (Figure 3a) were carried out using CD 3 OD and anhydrous sodium methoxide. The deuterated product was obtained in 90% deuteration and 83% yield, indicating that the double-bonded hydrogen in the product originated from methanol. Then, the alkenyl boron compound 3 was subjected under standard reaction conditions without B 2 pin 2. Product 2a was afforded in 82% yield, which suggests that 3 may be the possible reaction intermediate (Figure 3b).

Materials and Methods
All experiments were conducted under argon atmosphere. All commercially available reagents were purchased and used without further purification, unless otherwise stated. Flash chromatographic separations were carried out on 200-300 mesh silica gel. Reactions were monitored by TLC and GC analysis of reaction aliquots. GC analysis was performed on an Agilent 7890 gas chromatograph using an HP-5 capillary column (30 m × 0.32 mm, 0.5 µm film) with appropriate hydrocarbons as internal standards. 1 H, 13 C, and 19 F NMR spectra were recorded in CDCl 3 on a Bruker AVANCE III spectrometer and calibrated using residual undeuterated solvent (CDCl 3 at 7.26 ppm 1 H NMR, 77.16 ppm 13 C NMR). Chemical shifts (δ) are reported in ppm and coupling constants (J) are in Hertz (Hz). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. High resolution spectra (HRMS) were recorded on a QTOF mass analyzer with electrospray ionization (ESI) through a Waters G2-XS QTOF mass spectrometer.
According to the general procedure on a 1.0 mmol scale, the product was obtained in 72% yield (142.7 mg) as a colorless oil after silica gel column chromatography (PE (Z)-4-acetylstilbene (2j) [70].
According to the general procedure on a 1.0 mmol scale, the product was obtained in 60% yield (153.8 mg) as a white solid after silica gel column chromatography (PE (Z)-1-styrylnaphthalene (2m) [71].
According to the general procedure on a 1.0 mmol scale, the product was obtained in 54% yield (123.6 mg) as a colorless oil after silica gel column chromatography (PE (Z)-2-styrylthiophene (2n) [26].
According to the general procedure on a 1.0 mmol scale, the product was obtained in 98% yield (176.7 mg) as a white solid after silica gel column chromatography (PE). M.p. 119.7-120.

Conclusions
In conclusion, we developed an efficient semi-hydrogenation of alkynes that yields Z-olefins with high stereoselectivity and moderate to high yields. The method features the advantages of convenient and facile reaction conditions, wide substrate scope, and high stereoselectivity. Preliminary mechanistic studies suggest that the cis-intermediate 3 generated by insertion might be a critical intermediate in this transformation. Further studies on the mechanism of this strategy and its application in organic synthesis are still in progress.