Versatile cobalt-catalyzed regioselective chain-walking double hydroboration of 1,n-dienes to access gem-bis(boryl)alkanes

Double hydroboration of dienes is the addition of a hydrogen and a boryl group to the two double bonds of a diene molecule and represents a straightforward and effective protocol to prepare synthetically versatile bis(boryl)alkanes, provided that this reaction occurs selectively. However, this reaction can potentially yield several isomeric organoboron products, and it still remains a challenge to control the regioselectivity of this reaction, which allows the selective production of a single organoboron product, in particular, for a broad scope of dienes. By employing a readily available cobalt catalyst, here we show that this double hydroboration yields synthetically useful gem-bis(boryl)alkanes with excellent regioselectivity. In addition, the scope of dienes for this reaction is broad and encompasses a wide range of conjugated and non-conjugated dienes. Furthermore, mechanistic studies indicate that this cobalt-catalyzed double hydroboration occurs through boryl-directed chain-walking hydroboration of alkenylboronates generated from anti-Markovnikov 1,2-hydroboration of 1,n-diene.

In recent years, cobalt compounds have been extensively studied as catalysts for hydroboration and isomerization of alkenes [55][56][57][58][59][60][61][62][63] . In 2015, Chirik and coworkers showed one example of cobalt-catalyzed hydroboration of a boryl-containing terminal alkene to give a gem-bis(boryl)alkane product by taking the advantage of boryl-directed alkene isomerization 59 . During our continuous efforts in developing cobalt-catalyzed hydroboration of unsaturated hydrocarbons 64-66 , we become interested in identifying a selective cobalt catalyst for double hydroboration of 1,n-dienes to synthesize gem-bis(boryl)alkanes. We envisioned that it would be more challenging to develop a selective double hydroboration of aryl-substituted 1,n-dienes because both aryl and boryl groups in alkenylboronate products of the first hydroboration can control the direction of subsequent alkene isomerization, which would probably decrease the selectivity for the second hydroboration. Indeed, such decreased selectivity has been encountered in a recent study on NiH-catalyzed remote hydroarylation of a phenyl-containing alkenylboronate 54 . Here, we show that double hydroboration of these 1,n-dienes takes place to yield synthetically versatile gem-bis(boryl)alkanes with high regioselectivity in the presence of Co(acac) 2 and 1,2-bis (dicyclohexylphosphino)ethane (dcpe).

Results
Evaluation of reaction conditions. We chose the reaction of (E)octa-3,7-dien-1-ylbenzene (1a) with HBpin to identify a cobalt catalyst and the conditions that favor the formation of the gembis(boryl)alkane product 2a (Fig. 2). The cobalt catalysts we intended to evaluate were generated in situ from Co(acac) 2 and bisphosphine ligands and activated by the reaction with HBpin. In general, the targeted double hydroboration reactions were conducted with 2 mol% cobalt catalyst in the presence of 2.5 equivalents of HBpin for 4 h at 100°C. The selected examples of these reactions are summarized in Fig. 2.
The reaction conducted with Co(acac) 2 and dppe proceeded sluggishly to very low conversion (<5%) of 1a and the desired product 2a was not formed (Fig. 2, entry 1). The reaction catalyzed by Co(acac) 2 and dppbz occurred to a low conversion (33%) of 1a and only a trace amount of 2a was detected together with several other isomeric 1,n-dienes that were resulted from the isomerization of 1a (Fig. 2, entry 2). The reactions of 1a with HBpin afforded alkenylboronate 2a′ as a major product when conducted with Co(acac) 2 and dppp or dppb ligand (Fig. 2, entries 3 and 4). The reactions run with Co(acac) 2 and dppf, dpephos, or xantphos afforded eight isomeric bis(boryl)alkane products (Fig. 2, entries 5−7), and the selectivity for the desired product 2a was only low to modest (28−56%). To our delight, the reaction catalyzed by 2 mol % Co(acac) 2 /dcpe produced 2a in good yield (72%) and high regioselectivity (95% rr, Fig. 2, entry 8). In particular, the reaction conducted with 3 mol% catalyst afforded 2a in high isolated yield (76%) with excellent regioselectivity (97% rr, Fig. 2, entry 9). We also tested various temperatures for this double hydroboration reaction catalyzed by Co(acac) 2 /dcpe. Similar results were obtained for the reactions run at 100°C and 80°C (Fig. 2, entries 8 and 10). Further lowering the temperature to 50°C led to a lower yield of 2a with a diminished regioselectivity (Fig. 2, entry 11). Particularly, the reaction performed at room temperature afforded only the alkenylboronate product 2a′, which was formed from hydroboration of the terminal double bond of 1a (Fig. 2, entry 12).

Discussion
We subsequently conducted a series of experiments to gain insights into the mechanism of this cobalt-catalyzed double hydroboration reactions of 1,n-dienes, and the results of these experiments are summarized in Fig. 6. Similar to monohydroboration of 1,5-diene 1a at room temperature (Fig. 2, entry  12), monohydroboration of 1,3-diene 1s with 1.1 equiv. of HBpin occurred to completion in 30 min at room temperature and afforded alkenylboronate 11s selectively (Fig. 6a). Subsequent heating the reaction mixture at 100°C for 2 h resulted in the isomerization of 11s to a mixture of alkenylboronates 11s, 11s′, and 11s″ with a ratio of 51:17:32 (Fig. 6a). We then tested a mixture of these alkenylboronates for hydroboration with HBpin in the presence of 1 mol % of Co(acac) 2 /dcpe, and all these isomeric alkenylboronates were converted to gem-bis(boryl)alkane 2s in high yield (Fig. 6b). The conversion of 11s, 11s′, and 11s″ to a single product 2s indicates that boryl group has a stronger directing ability for this cobalt-catalyzed chain-walking hydroboration than phenyl group, which may stem from the interaction of the d-electrons of the cobalt catalyst with the empty p-orbital on boron 68 . A control experiment of this double hydroboration was conducted with a substrate containing an oxygen-tethered 1,6-diene      (Fig. 6c). This reaction afforded 1,7-bis(boryl)alkane 13 and chain-walking double hydroboration was not observed. This suggests that the chain walking takes place through reversible βhydrogen elimination and reinsertion steps. A deuterium-labeling experiment of the double hydroboration of 1,3-diene (E)-1s was then conducted with DBpin, and deuterium incorporation at all positions of the aliphatic chain of gem-bis(boryl)alkane 2s-D was observed (Fig. 6d). When the deuterium-labeling experiment was performed with (E)-1s-D and HBpin, deuterium scrambling at all positions of the aliphatic chain of 2s-D was observed as well (Fig. 6d). In addition, when a crossover experiment of this double hydroboration was run with (E)-1s-D and (E/Z)-1×, similar deuterium incorporation and deuterium scrambling map was also observed for gem-bis(boryl)alkane products 2s-D and 2×-D (Fig. 6e). The results of this crossover experiment indicate that dissociation and re-association of Co-H/D from the Co-H/Dolefin complex occurs during the chain walking process.
In addition, we also tested a cobalt catalyst generated from Co (acac) 2 and dppe (1,2-bis(diphenylphosphino)ethane), a bisphosphine ligand having a similar steric but different electronic property, for hydroboration of terminal alkenes 18 and 19 with HBpin ( Fig. 7e and f). These two reactions proceeded very sluggishly and approximately 30% of 18 and 19 were converted at 100°C in 24 h. Interestingly, major products (16 and 21) of these two reactions were resulted from direct anti-Markovnikov hydroboration of 18 and 19, and much less byproducts (15 and 20) were formed by chain-walking hydroboration relative to the corresponding reactions catalyzed by the cobalt catalyst generated from Co(acac) 2 and dcpe (Fig. 7c, d). The results of these four reactions (Fig. 7c-f) suggest that the electron-rich property of dcpe ligand facilitates the chain-walking process, thus promoting chain-walking hydroboration.
Based on the results of mechanistic studies, we proposed a catalytic pathway for this cobalt-catalyzed chain-walking double hydroboration of 1,4-diene 1b, as depicted in Fig. 8. The activation of Co(acac) 2 with HBpin in the presence of dcpe (L) forms a cobalt hydride species (L)Co-H (ref. 69 ). Migratory insertion of the terminal alkene of 1b into (L)Co-H generates an alkenylcobalt intermediate A, which then undergoes σ-bond metathesis with HBpin to produce alkenylboronate 2b′ and regenerates (L)Co-H. The double bond in 2b′ then inserts into (L)Co-H to form an alkylcobalt species B, which undergoes isomerization to form the alkylcobalt intermediate C through reversible β-hydrogen elimination and reinsertion. In the last step, σ-bond metathesis between alkylcobalt species In summary, we have developed an effective and convenient protocol to prepare gem-bis(boryl)alkanes via a selective cobaltcatalyzed double hydroboration of 1,n-dienes. A wide range of conjugated and non-conjugated 1,n-dienes reacted with pinacolborane to produce gem-bis(boryl)alkanes in high isolated yields with excellent regioselectivity in the presence of a catalyst generated in situ from Co(acac) 2 and dcpe ligand. Mechanistic studies suggest that this cobalt-catalyzed double hydroboration occurs through an initial anti-Markovnikov monohydroboration of 1,n-dienes followed by a sequential boryl-directed chainwalking hydroboration of the resulting alkenylboronates. This cobalt-catalyzed double hydroboration provides a straightforward approach to access structurally diverse and synthetically versatile gem-bis(boryl)alkanes from readily available 1,n-dienes.

Methods
General procedure for double hydroboration of 1,n-dienes. In an Argon-filled glovebox, a 4-mL screw-capped vial was charged with Co(acac) 2 (0.8 mg, 3.0 µmol), dcpe (1.3 mg, 3.0 μmol), 1,n-diene (0.30 mmol), heptane (0.5 mL) and a magnetic stirring bar. The solution was stirred for 5 min and pincolborane (96.0 mg, 0.75 mmol) was added to the vial. The vial was sealed with a cap containing a PTFE septum and removed from the glovebox. The mixture was then heated at 100°C for 4 h until complete consumption of starting material as monitored by TLC and GC-MS analysis. Subsequently, the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane/ethyl acetate = 40:1) to afford the desired products. See the Supplementary Information for detailed experimental procedures and the characterization data of all the products.