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]