What Is Brown Hydroboration Reaction?
The Brown hydroboration reaction was reported by H.C. Brown in 1956. Alkenes react with sodium borohydride (NaBH4) in the presence of aluminum chloride (AICl3) to obtain cis-anti-Markovnikov rule addition products to the olefins, which are then oxidized to the corresponding hydroxyl compounds under the action of hydrogen peroxide. H.C. Brown shared the 1979 Nobel Prize in Chemistry with G. Wittig for the discovery and research of this reaction. This reaction enables the anti-Markovnikov addition of boron hydrides (BH3 derivatives) to alkenes, producing organoboranes that serve as versatile intermediates in organic synthesis.
- Reagents: Borane (BH3) in a complex (e.g., BH3-THF, BH3-DMS), or a substituted borane (e.g., 9-BBN, disiamylborane, catecholborane).
- Reactants: Alkenes or alkynes.
- Products: Organoboranes (which are then typically converted into other functional groups). Common examples after workup are alcohols (via oxidation).
- Reaction type: Reduction reaction.
- Related reaction: Suzuki-Miyaura coupling, Corey-Bakshi-Shibata reduction.
Fig 1. Brown hydroboration reaction and its mechanism. [1]
Mechanism of Brownian Hydroboration
Sodium borohydride (NaBH4) reacts with boron trifluoride ethyl ether (BF3·Et2O) to produce borane. Borane cannot exist in a free state and generally exists in the form of a dimer diborane (B2H6). Diborane has 12 electrons, 8 of which form 4 B-H bonds. On one plane, the other 4 electrons form 2 three-center two-electron bonds, one above and one below the plane.
When organic ether compounds (diethylene glycol dimethyl ether, tetrahydrofuran, diethyl ether) are used as solvents, diborane dissociates into a complex of borane-ether (R2O-BH3). The reaction of borane with olefins proceeds smoothly at room temperature. Hydrogen is added to carbon atoms with fewer double-bonded hydrogen atoms. The reaction passes through a four-center transition state. Because the reaction does not pass through a carbon cation intermediate, the substituents of each carbon atom maintain their original relative positions, and a cis-anti-Markovnikov rule addition product with stereospecificity for the olefin is obtained.
Experimental Tips
- Borane (B2H6) can also be generated by the reaction of lithium aluminum hydride (LiAlH4) with (BF3·Et2O), without the need for diglyme as a solvent in the reaction.
- In the reaction, borane attacks from the less hindered surface. For example, the Brown hydroboration of norbornene produces exo-norborneol with high selectivity.
- When the olefin is a non-terminal olefin, the hydroboration of borane and olefin is regioselective, and boron is preferentially added to the double bond carbon with less hindrance, but the regioselectivity is generally not high. For example, the Brown hydroboration of 2-hexene and borane produces a mixture of 2-hexanol and 3-hexanol.
- Olefins and borane addition products can also transform into respective amine compounds or react further with α,β-unsaturated carbonyl compounds. During the Brown hydroboration of diene compounds non-conjugated olefins show greater reactivity than conjugated olefins while intracyclic conjugated olefins demonstrate higher reactivity compared to exocyclic conjugated olefins.
Application Examples of Brown Hydroboration
- Example 1: In the asymmetric total synthesis strategy for the alkaloid (+)-strictamine, the diastereoselective Brown hydroboration of terminal olefins to introduce the C16 stereocenter is a key step. [2]
- Example 2: Mopuri Sudhakar Reddy et al. reported the first stereoselective total synthesis of the anti-inflammatory metabolite penicillinolide A. They used BH3·SMe2 (BMS) and hydrogen peroxide to hydroborate-oxidize the terminal olefin to afford the primary alcohol in 80% yield. [3]
Fig 2. Synthetic examples via Brown hydroboration reaction.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 50-52.
- Chen, Zhi-Tao, et al. Tetrahedron, 2018, 74(11), 1129-1134.
- Reddy, Mopuri Sudhakar, et al. Synthesis, 2019, 51(06), 1427-1434.
