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Buchwald-Hartwig Amination

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General Overview

The Buchwald-Hartwig (B-H) amination or coupling reaction is a catalytic reaction widely used for the construction of sp2-N carbon-nitrogen bonds from amines and aryl/heteroaryl halides or sulfonates. Typically the B-H amination is employed when the desired carbon-nitrogen bond cannot be formed by a classical SNAr reaction due to low reactivity of the aryl/heteroaryl coupling partner.

Typically coupling partners are halides, sulfonates, triflates, mesylates, tosylates and primary and secondary amines. Primary amines can be prepared from ammonia equivalents like benzophenone imine or even NH3 itself. Other nitrogen sources like amides or sulfonamides are occasionally used as amine coupling partners. The aryl/heteroaryl halide is reacted with the amine in the presence of a Pd catalyst – either a Pd(0) or Pd (2+) salt/complex. And a ligand – usually a phosphine or carbene -in the presence of a base. Alternatively, a pre-formed catalytic complex can be added.

From an environmental perspective, the B-H amination reaction has a number of challenges. Historically it has used Palladium, a precious metal with high carbon footprint and with a high environmental impact for extraction and purification. The reaction may also  require complex ligands with a high footprint and undesirable solvents such as toluene, xylene and 1,4-dioxane.

As an alternative to the use of Pd, a growing number of publications use base metal catalysis for B-H-like coupling reactions to make amines. Many of these are variants of the Ullman reaction using Cu as the catalyst, but in combination with various ligands to increase the activity of the catalyst to allow operation under much milder conditions/lower temperatures than found with traditional Ullman chemistry. Other metals like Ni are reported to be active in B-H reactions.

 

Green Criteria for Buchwald-Hartwig Amination

  1. Large molar excesses of reagents should be avoided if possible.
  2. Ideally reduction with H2/metal catalyst is the preferred reductant
    Chem. Soc. Rev., 2014, 43, 3525-3550 Copper catalysed Ullmann type chemistry: from mechanistic aspects to modern development
  3. If ligands are used, simple, low Mol Wt materials are preferable.
  4. Metal and ligand loadings should be optimised.
  5. Simple inorganic bases are preferred to organic amine bases and alkoxides
  6. Original publications on B-H amination used aminostannanes as coupling partners-it was later demonstrated that the use of organotin derivatives is not required.
  7. High impact solvents like 1,4-dioxane should be avoided if possible.
  8. Work-up/DSP should ensure metal levels are reduced to relevant specifications in the product and any waste streams, and if a Pd catalyst, or other precious metal, is used recovery and recycle of the metal is optimised.
  9. Consideration should be given to catalysis of the traditional SNAr pathway to avoid the use of metals if possible, or a more direct route via C-H activation
    ChemSusChem, 2013, 6, 1455 – 1460 Amination of Heteroaryl Chlorides: Palladium Catalysis or SNAr in Green Solvents?
    Org. Process Res. Dev. 2013, 17, 672−678 Acid catalysis


    Chem. Soc. Rev., 2011, 40, 5068-5083 Recent advances in the transition metal-catalyzed two fold oxidative C–H bond activation strategy for C–C and C–N bond formation
  10. Due to the number of variables, design of experiments and principal components analysis can be a useful tool to optimise B-H amination reactions, and ligand selection.
    Journal of Chemical Technology and Biotechnology, 2014, 89 (5), 623-632. Ligand and solvent selection in challenging catalytic reactions
     Optimisation of a Demanding Buchwald-HartwigAmination
    Optimizing Organic Reactions with Design of Experiments and Principal Component Analysis

 

General Reviews for Buchwald-Hartwig coupling

Chem. Rev., 2006, 106,  2651–2710 Selected Patented Cross-Coupling Reaction Technologies

J. Am. Chem. Soc., 1994, 116, 5969–5970 Palladium-catalyzed formation of carbon-nitrogen bonds. Reaction intermediates and catalyst improvements in the hetero cross-coupling of aryl halides and tin amides

J. Am. Chem. Soc., 1994, 116, 7901–7902 Palladium-Catalyzed Aromatic Aminations with in situ Generated Aminostannanes

Chem. Rev., 2011, 111 (3), pp 2177–2250 Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals

Chem. Soc. Rev., 2011, 40, 5151-5169 N-Heterocyclic carbene (NHC) ligands and palladium in homogeneous cross-coupling catalysis: a perfect union

Chem. Soc. Rev., 2011, 40, 4963-4972 Palladium-catalyzed cross-coupling reactions of aryl mesylates

Chem. Soc. Rev., 2013, 42, 9283-9303 C–N bond forming cross-coupling reactions: an overview

Transition Metal-Catalyzed Couplings in Process Chemistry Wiley 2013

Metal-Catalyzed Cross-Coupling Reactions and More Chp 13 Palladium-Catalyzed Aromatic Carbon–Nitrogen Bond Formation Wiley 2013

www.organic-chemistry.org/namedreactions/buchwald-hartwig-reaction.shtm

en.wikipedia.org/wiki/Buchwald%E2%80%93Hartwig_amination

Chem. Soc. Rev., 2008, 37, 639-647 Palladium and copper-catalysed arylation reactions in the presence of water, with a focus on carbon–heteroatom bond formation