Borylation

In organic chemistry, metal-catalyzed C–H borylation reactions constitute a family of organic reactions in which a transition metal catalyst activates aliphatic or aromatic C–H bonds to produce an organoboron compound (i.e., a C–B bond). They are thus functionalization reactions and a form of carbon–hydrogen bond activation. Compared to traditional polar reactions that introduce boron into a molecule, they obviate preparatory functionalization, eschew toxic byproducts, and (in some cases) functionalize a different part of the same substrate.: 24–25, 27–28 

The net reaction for a borylation is generally a single displacement of the form

R2B−BR2 + R'H → R2BH + R'BR2

The R2B−BR2 structure is rather unusual, but known in bis(pinacolato)diboron (B2Pin2), bis(catecholato)diborane (B2Cat2), diboron tetrachloride, and tetrahydroxydiboron.

Primary versus secondary metal-alkyl complex

Mechanistically, the reaction resembles a noble-metal-catalyzed coupling reaction, and proceeds through cycles of oxidative addition followed by reductive elimination. First, the catalyst inserts into the boron-boron bond, forming a diboryl complex before eliminating one hydroboronic acid equivalent. Then it inserts into a carbon-hydrogen bond, forming a heteroleptic hydride-boryl-alkyl complex, before eliminating the product.

Aliphatic borylation

As Hartwig first described in 2000, alkanes can be highly-selectively borylated at the primary C–H bond using catalytic Cp*Rh(η4-C6Me6). Notably, the catalyst completely ignores heteroatoms, instead borylating exclusively primary C–H bonds. For acetals, ethers, amines, and alkyl fluorides with multiple primary C–H bonds, borylation occurs at the most sterically clear and electron-poorest such bond.

Aliphatic C–H borylation
Aliphatic C–H borylation
C–H borylation of polyolefins
C–H borylation of polyolefins

The rhodium complex catalyzes no reaction when the substrate lacks primary C–H bonds, for example cyclohexane. Ir(Mes)(BPin)3 or (Ir(cod)OMe)2 catalyze borylation selectively at secondary C–H bonds in the presence of tertiaries.: 179–205 

The catalysts' selectivities arise from both thermodynamic and kinetic effects. The relative steric clearance around less-substituted C–H bonds enables preferential attack by the relatively bulky catalysts. Typically, the bonds are also slightly more acidic, stabilizing the resulting complex. In the next step, primary alkyl ligands reductively eliminate with a boryl ligand more easily than do secondary ligands:

Mechanistic pathways for aliphatic C–H borylation
Mechanistic pathways for aliphatic C–H borylation

Catalysis with iron or tungsten carbonyl complexes is also possible, but requires irradiation to dissociate carbonyl ligands during the catalytic cycle.

Aromatic borylation

Aryl borylation is more complicated than its aliphatic counterpart, as the different locations are less different sterically. In some cases, electronic effects dominate.

In the simplest case, a catalyst generated in situ from [Ir(COD)(OMe)]2 and 4,4′-di-tert-butylbipyridine (dtbpy) catalyzes borylation with an ortho:meta:para ratio of roughly 0:2:1 on a wide variety of substrates:

Meta-para borylation
Meta-para borylation
Steric-directing iridium-catalyzed C–H borylation
Steric-directing iridium-catalyzed C–H borylation

A benzylic hydrosilyl group directs ortho substitution instead. The catalyst preferentially but reversibly attacks the hydrosilyl bond, holding it at the right geometry to then borylate the ortho position:

Mechanism of hydrosilane
Mechanism of hydrosilane

Traditional directed ortho substitution relies on chelation to a nearby Lewis basic moiety,: 8–15  and cannot be achieved when bidentate dtbpy is part of the active catalyst. Contrariwise, it occurs when certain monodentate ligands, including tris(3,5-bis(trifluoromethyl)phenyl)phosphine and an immobilized phosphine, replace dtbpy. Likewise, it occurs when certain bidentate-but-hemilabile ligands, including dibenzyl pyridinal hydrazone and 8‑aminoquinoline, replace dtbpy.

Increasing the meta product proportion is also possible through chelation. The BPin moieties on the active catalyst are Lewis acidic, and coordinate to (e.g.) benzaldimines. Similarly, an appropriately chosen bipyridine-urea ligand can hydrogen bond to a benzoyl oxygen to achieve meta selectivity.

Heteroarene borylation is much more sensitive to electronic effects; furans, pyrroles, and thiophenes undergo reaction at the C–H bond adjacent to the heteroatom. The selectivity is suggested to occur because the cloven bond is the most acidic and therefore most reactive.

C–H borylation of heteraromatics

History

The first example of a catalytic C–H borylation of an unactivated hydrocarbon (benzene) was reported by Smith and Iverson using Ir(Cp*)(H)(Bpin) as the catalyst. The efficiency of this system, however, was low, providing only 3 turnovers after 120 h at 150 °C. Numerous subsequent developments by Hartwig and coworkers led to efficient, practical conditions for arene borylation.

Aromatic C–H functionalization was successfully incorporated in the total synthesis of Complanadine A, a Lycopodium alkaloid that enhances mRNA expression for nerve growth factor (NGF) and the production of NGF in human glial cells. Natural products that promote the growth of new neural networks are of interest in the treatment of diseases such as Alzheimer's disease. Complanadine A was successfully synthesized using a combination of direct aromatic C–H borylation developed by Hartwig and Ishyiama, followed by Suzuki–Miyaura cross coupling, then cleavage of the Boc protecting group.

Synthesis of complanadine A
Synthesis of complanadine A

See also

References

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  4. ↑ Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chem. Commun. 2003, 2924.
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  6. ↑ Hommer, Herbert; Nöth, Heinrich; Knizek, Jörg; Ponikwar, Werner; Schwenk-Kircher, Holger (1998) [May 8, 1998]. "Synthesis and structures of dimesityldiboranes(4)". Eur. J. Inorg. Chem. Wiley-VCH: 1519–1527. doi:10.1002/(SICI)1099-0682(199810)1998%3A10<1519%3A%3AAID-EJIC1519>3.0.CO%3B2-%23.
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  10. ↑ Kondo, Y.; Garcia-Cuadrado, D.; Hartwig, J. F.; Boaen, N. K.; Wagner, N. L.; Hillmyer, M. A. (2002). "Rhodium-Catalyzed, Regiospecific Functionalization of Polyolefins in the Melt". J. Am. Chem. Soc. 124 (7): 1164–5. Bibcode:2002JAChS.124.1164K. doi:10.1021/ja016763j. PMID 11841273.
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  12. ↑ Wei, C. S.; Jimenez-Hoyos, C. A.; Videa, M.F.; Hartwig, J. F.; Hall, M. B. (2010). "Origins of the Selectivity for Borylation of Primary over Secondary C−H Bonds Catalyzed by Cp*-Rhodium Complexes". J. Am. Chem. Soc. 132 (9): 3078–91. Bibcode:2010JAChS.132.3078W. doi:10.1021/ja909453g. PMID 20121104.
  13. ↑ Mkhalid, Ibraheem A. I.; Barnard, Jonathan H.; Marder, Todd B.; Murphy, Jaclyn M.; Hartwig, John F. (2010). "C-H Activation for the Construction of C-B Bonds". Chemical Reviews. 110: 893–894. doi:10.1021/cr900206p.
  14. ↑ Boller, T.M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J.F. J. Am. Chem. Soc. 2005;, 127, 14263.
  15. 1 2 Hartwig, J.F. (2012). "Borylation and silylation of C-H bonds: a platform for diverse C-H bond functionalizations". Accounts of Chemical Research. 45 (6): 864–873. doi:10.1021/ar200206a. PMID 22075137.
  16. ↑ Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N.; Hartwig, J.F. (2002). "Mild Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate". J. Am. Chem. Soc. 124 (3): 390–391. Bibcode:2002JAChS.124..390I. doi:10.1021/ja0173019. PMID 11792205.
  17. ↑ Boebel, T. A.; Hartwig, J. F. (2008). "Silyl-Directed, Iridium-Catalyzed ortho-Borylation of Arenes. A One-Pot ortho-Borylation of Phenols, Arylamines, and Alkylarenes". J. Am. Chem. Soc. 130 (24): 7534–5. Bibcode:2008JAChS.130.7534B. doi:10.1021/ja8015878. PMID 18494474.
  18. ↑ Ishiyama, T.; Miyaura, N.; Isou, H.; Kikuchi, T. (2010). "Ortho-C–H borylation of benzoate esters with bis(pinacolato)diboron catalyzed by iridium–phosphine complexes". Chem. Commun. 46 (1): 159–61. doi:10.1039/b910298a. hdl:2115/44631. PMID 20024326.
  19. ↑ Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. (2009). "Directed Ortho Borylation of Functionalized Arenes Catalyzed by a Silica-Supported Compact Phosphine−Iridium System". J. Am. Chem. Soc. 131 (14): 5058–9. Bibcode:2009JAChS.131.5058K. doi:10.1021/ja9008419. PMID 19351202.
  20. ↑ Ros, A.; Estepa, B.; Lopez-Rodriquez, R.; Alvarez, E.; Fernandez, R.; Lassaletta, J.M. Angew. Chem. Int. Ed. 2011; 50, 1.
  21. 1 2 Bisht, R.; Chattopadhyay, B. (2016). "Formal Ir-Catalyzed Ligand-Enabled Ortho and Meta Borylation of Aromatic Aldehydes via in Situ-Generated Imines". J. Am. Chem. Soc. 138 (1): 84–7. Bibcode:2016JAChS.138...84B. doi:10.1021/jacs.5b11683. PMID 26692251.
  22. ↑ Kanai; et al. (2015). "A meta-selective C–H borylation directed by a secondary interaction between ligand and substrate". Nat. Chem. 7 (9): 712–7. Bibcode:2015NatCh...7..712K. doi:10.1038/nchem.2322. PMID 26291942.
  23. ↑ Iverson, Carl N.; Smith, Milton R. (1999-08-06). "Stoichiometric and Catalytic B−C Bond Formation from Unactivated Hydrocarbons and Boranes". Journal of the American Chemical Society. 121 (33): 7696–7697. Bibcode:1999JAChS.121.7696I. doi:10.1021/ja991258w.
  24. ↑ Fischer, D.F; Sarpong, R. (2010). "Total Synthesis of (+)-Complanadine A Using an Iridium-Catalyzed Pyridine C−H Functionalization". J. Am. Chem. Soc. 132 (17): 5926–5927. Bibcode:2010JAChS.132.5926F. doi:10.1021/ja101893b. PMC 2867450. PMID 20387895.