Hauser base

Hauser bases, also called magnesium amide bases, are magnesium compounds used in organic chemistry as bases for metalation reactions. These compounds were first described by Charles R. Hauser in 1947. ^[1] Compared with organolithium reagents, the magnesium compounds have more covalent, and therefore less reactive, metal-ligand bonds. Consequently, they display a higher degree of functional group tolerance and a much greater chemoselectivity. ^[2] Generally, Hauser bases are used at room temperature while reactions with organolithium reagents are performed at low temperatures, commonly at −78 °C.

Structures

Hauser bases have the empirical formula R₂NMgX (X = halide). The crystallize as dimers with halide bridges. Attached to Mg is amido (R₂N) ligands derived from secondary amines 2,2,6,6-tetramethylpiperidine (TMP⁻) and HMDS ⁻). ^{[3] [4] [5]}

Amido-bridged Hauser bases exist when the amido ligand is less bulky, such as Et₂N⁻ and Ph₃P=N⁻. ^{[4] [6] [7]}

• Structures of Selected Hauser Bases (H atoms removed for clarity)
• 
  TMP Hauser Base
• 
  HMDS Hauser Base
• 
  Diethylamido Hauser Base

The structures of Hauser bases in solution have been investigated by diffusion-ordered NMR spectroscopy (DOSY). ^[8] These studies indicate that iPr₂NMgCl is subject to the Schlenk equilibrium: ^[9]

iPr₂NMgCl (A) ⇌ (iPr₂N)₂Mg (B) + MgCl₂

This equilibrium is temperature-dependent: heteroleptic (A) are the main species at high temperatures and homoleptic (B) dominate at lower temperatures. Dimeric species with bridging chlorides and amides are also present in the THF solution. At low temperatures, adducts of MgCl₂ are present in solution. ^[9]

Preparation and reactions

The Hauser bases are prepared by treating a secondary amine with a Grignard reagent:

R₂NH + R′MgX → R₂NMgX + R′H  X = Cl, Br, I

(:R₂NH = diisopropylamine, TMP)

Like many organolithium reagents, Hauser bases are generally used for metalation reagents. iPr₂NMgBr selectively magnesiate carboxamides. ^[10] iPr₂NMgX (X = Cl, Br) effect the deprotonation thiophenes. ^[11] and phenylsulphonyl-substituted indoles. ^[12]

Turbo-Hauser base

Main article: Turbo-Hauser bases

A major disadvantage of Hauser bases is their poor solubility in THF. In consequence, the metalation rates are slow and a large excess of base is required (e.g., 10 equiv.). This circumstance complicates the functionalization of the metaled intermediate with an electrophile. Improved solubility and reactivity can be achieved by adding stoichiometric amounts of LiCl to the Hauser base. These so-called Turbo-Hauser bases like e.g. TMPMgCl·LiCl and iPr₂NMgCl·LiCl are commercially available. They show an enhanced kinetic basicity, regioselectivity and functional group tolerance. ^[13]

References

1. Hauser C. R., Walker H (1947). "Condensation of Certain Esters by Means of Diethylaminomagnesium Bromide". J. Am. Chem. Soc. 69 (2): 295. doi:10.1021/ja01194a040.
2. Li–Yuan Bao, R.; Zhao, R.; Shi, L. (2015). "Progress and developments in the turbo Grignard reagent i-PrMgCl·LiCl: a ten-year journey". Chem. Commun. 51 (32): 6884–6900. doi:10.1039/C4CC10194D. PMID   25714498.
3. e.g.; Seven, Ö.; Bolte, M.; Lerner, H.-W. (2013). "Di-μ-bromido-bis[(diethyl ether-κO)(2,4,6-trimethylphenyl)magnesium]: the mesityl Grignard reagent" (PDF). Acta Crystallogr. E . 69 (7): m424. doi:10.1107/S1600536813017108. PMC   3772445 . PMID   24046588.
4. García–Álvarez, P.; Graham, D. V.; Hevia, E.; Kennedy, A. R.; Klett, J.; Mulvey, R. E.; O'Hara, C. T.; Weatherstone, S. (2008). "Unmasking Representative Structures of TMP-Active Hauser and Turbo-Hauser Bases". Angew. Chem. Int. Ed. 47 (42): 8079–8081. doi: 10.1002/anie.200802618 . PMID   18677732.
5. Yang, K.-C.; Chang, C.-C.; Huang, J.-Y.; Lin, C.-C.; Lee, G.-H.; Wang, Y.; Chiang, M. Y. (2002). "Synthesis, characterization and crystal structures of alkyl-, alkynyl-, alkoxo- and halo-magnesium amides" (PDF). J. Organomet. Chem. 648 (1–2): 176–187. doi:10.1016/S0022-328X(01)01468-1.
6. Batsanov, A. S.; Bolton, P. D.; Copley, R. C. B.; Davidson, M. G.; Howard, J. A. K.; Lustig, C.; Price, R. D. (1998). "The metallation of imino(triphenyl)phosphorane by ethylmagnesium chloride: The synthesis, isolation and X-ray structure of [Ph₃P=NMgCl·O=P(NMe₂)₃]₂". J. Organomet. Chem. 550 (1–2): 445–448. doi:10.1016/S0022-328X(97)00550-0.
7. Armstrong D. R.; García–Álvarez, P.; Kennedy, A. R.; Mulvey, R. E.; Parkinson, J. A. (2010). "Diisopropylamide and TMP Turbo-Grignard Reagents: A Structural Rationale for their Contrasting Reactivities". Angew. Chem. Int. Ed. 49 (18): 3185–3188. doi: 10.1002/anie.201000539 . PMID   20352641.
8. Neufeld, R.; Stalke, D. (2015). "Accurate Molecular Weight Determination of Small Molecules via DOSY-NMR by Using External Calibration Curves with Normalized Diffusion Coefficients". Chem. Sci. 6 (6): 3354–3364. doi:10.1039/C5SC00670H. PMC   5656982 . PMID   29142693.
9. Neufeld, R.; Teuteberg, T. L.; Herbst-Irmer, R.; Mata, R. A.; Stalke, D. (2016). "Solution Structures of Hauser Base iPr₂NMgCl and Turbo-Hauser Base iPr₂NMgCl·LiCl in THF and the Influence of LiCl on the Schlenk-Equilibrium". J. Am. Chem. Soc. 138 (14): 4796–4806. doi:10.1021/jacs.6b00345. PMID   27011251.
10. Eaton, P. E.; Lee, C. H.; Xiong, Y. (1989). "Magnesium amide bases and amido-Grignards. 1. Ortho magnesiation". J. Am. Chem. Soc. 138 (20): 8016–8018. doi:10.1021/ja00202a054.
11. Shilai, M.; Kondo, Y.; Sakamoto, T. (2001). "Selective metallation of thiophene and thiazole rings with magnesium amide base". J. Chem. Soc. Perkin Trans. 1 (4): 442–444. doi:10.1039/B007376H.
12. Kondo, Y.; Yoshida, A.; Sakamoto, T. (1996). "Magnesiation of indoles with magnesium amide bases". J. Chem. Soc. Perkin Trans. 1 (19): 2331–2332. doi:10.1039/P19960002331.
13. Li-Yuan Bao, Robert; Zhao, Rong; Shi, Lei (2015). "Progress and Developments in the turbo Grignard Reagent i-PrMgCl·LiCl: A Ten-Year Journey". Chemical Communications. 51 (32): 6884–6900. doi:10.1039/c4cc10194d. PMID   25714498.