Cobalt catalyzed practical hydroboration of terminal alkynes with time-dependent stereoselectivity

Abstract

Stereodefined vinylboron compounds are important organic synthons. The synthesis of E-1-vinylboron compounds typically involves the addition of a B-H bond to terminal alkynes. The selective generation of the thermodynamically unfavorable Z-isomers remains challenging, necessitating improved methods. Here, such a proficient and cost-effective catalytic system is introduced, comprising a cobalt salt and a readily accessible air-stable CNC pincer ligand. This system enables the transformation of terminal alkynes, even in the presence of bulky substituents, with excellent Z-selectivity. High turnover numbers (>1,600) and turnover frequencies (>132,000 h^-1) are achieved at room temperature, and the reaction can be scaled up to 30 mmol smoothly. Kinetic studies reveal a formal second-order dependence on cobalt concentration. Mechanistic investigations indicate that the alkynes exhibit a higher affinity for the catalyst than the alkene products, resulting in exceptional Z-selective performance. Furthermore, a rare time-dependent stereoselectivity is observed, allowing for quantitative conversion of Z-vinylboronate esters to the E-isomers.

Fig. 1. Selective hydroboration of terminal alkynes catalyzed by earth-abundant metals.

a Comparison of three reported earth-abundant metal catalysts for achieving highly Z-selective hydroboration of terminal alkynes. The Z selectivity, highest turnover numbers (TONs), and turnover frequencies (TOFs) of each system are shown. b This work: an efficient and general cobalt catalyst system for hydroboration of terminal alkynes with time-dependent stereoselectivity. c Easy large-scale production of CNC-ⁱPr from inexpensive commercially available compounds with high isolated yields. Prices listed are sourced from bidepharm.com.

Fig. 2. Scope of Z-selective hydroboration of terminal alkynes.

Reaction conditions: terminal alkyne (1.0 equiv, 0.4 mmol), HBpin (1.3 equiv), Co(acac)₂ ([Co], 0.5 mol%), CNC-ⁱPr (1.4 equiv to [Co]), ^tBuOK (5.6 equiv to [Co]) in DMF (0.5 ml) at room temperature (r.t.). See Supplementary Information for experimental details. ¹H NMR yields are shown with methylene bromide or mesitylene as the internal standard. Isolated yields and Z/E ratios are provided in parenthesis. ^a0.1 mmol% Co(acac)₂, 0.8 mmol scale. ^b1 mmol% Co(acac)_2. ^c0.05 mmol% Co(acac)₂, yield determined by GC-MS. ^d24 h. ^e48 h. ^f2.5 equiv. HBpin. ^g3 equiv. HBpin. ^hWith 10 mol% diphenylacetylene, ⁱ0.2 mmol% Co(acac)_2. ^j2 equiv. HBpin.

Fig. 3. Large scale reaction.

Reaction conditions: terminal alkyne (1.0 equiv, 30 mmol), HBpin (1.3 equiv), Co(acac)₂ ([Co], as presented), CNC-ⁱPr (1.4 equiv to [Co]), ^tBuOK (5.6 equiv to [Co]) in DMF (35 ml) at 0 °C–room temperature (r.t.).

Fig. 4. Kinetic investigation.

a Proposed equilibrium equation of the hydroboration of terminal alkynes. b Kinetic profile of the hydroboration of phenylacetylene (1a). Reaction conditions: 1a (1.0 equiv, 0.4 mmol), HBpin (2.0 equiv), Co(acac)₂ ([Co], 0.5 mol%), CNC-ⁱPr (1.4 equiv to [Co]), ^tBuOK (5.6 equiv to [Co]) in DMF (0.5 ml) at room temperature (r.t.). c Kinetic analysis of the formal reaction order based on the concentration of catalyst ([Co]). d Time-dependent stereoselective hydroboration of terminal alkynes. Reaction conditions: terminal alkyne (1.0 equiv, 0.4 mmol), HBpin (3.0 equiv), Co(acac)₂ ([Co], 0.5–5 mol%), CNC-ⁱPr (1.4 equiv to [Co]), ^tBuOK (5.6 equiv to [Co]) in DMF (0.5 ml) at room temperature (r.t.). See Supplementary Information for experimental details. ¹H NMR yields are shown with methylene bromide as the internal standard. Isolated yields and Z/E ratios in parenthesis. The reaction time for the transformation of the E isomers was not optimized.

Fig. 5. Mechanistic study.

a Deuterium labeling experiments. b Inhibition of Z/E isomerization with an inert alkyne. c Kinetic trace of Z-selective products for reactions employing 1a, 9a, and mixture of 1a and 9a, respectively. Products of the mixed system have been marked in the profile. Reaction conditions: terminal alkyne (1.0 equiv, 0.4 mmol), HBpin (1.3 equiv), Co(acac)₂ ([Co], 0.5 mol%), CNC-ⁱPr (1.4 equiv to [Co]), ^tBuOK (5.6 equiv to [Co]) in DMF (0.5 ml) at room temperature (r.t.). d High Resolution Mass Spectrometry (HRMS) of [Co(II)(CNC-ⁱPr)Br]⁺. e X-ray structure of [Co(III) (CNC-ⁱPr)₂]Br₃. Hydrogen, bromine, and solvent atoms are omitted for clarity. See Supplementary Fig. 14 and Supplementary Tables 13–15 for details. f Proposed mechanism. The positions of the colored hydrogen atoms have been traced by the deuterium labeling experiments (a).