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Catalytic Asymmetric Allylic Amination

Mechanism + Description

Under the influence of a metal catalyst, a suitably substituted allyic reagent  binds to  a catalytic centre with the expulsion of a leaving group e.g. acetate. The resulting coordinated π- allyl cation can then react with a nuclophile to generate the allyic amine and regenerate the metal catalyst.

General comments

A reaction of wide utility but scope limited to allylic substrates with leaving groups able to form metal coordinated  π- allyl cations. Leaving groups include carbonates, phosphate and acetate. Notably, Hartwig has achieved high ee with use of amines and allylic alcohols with only OH as the leaving group. These coordinated pi allyl cations can react with a variety of reagents, especially nitrogen nucleophiles of a wide scope, including alkyl amines, heterocyclic amines, aromatic amines, azide, sulfonamide, imide, guanidines, and sulfamic acid. The reaction is readily amenable to scale-up.

Key references

Org. Process Res. Dev., 2012, 16, 185–194 Pd- and Mo-Catalyzed Asymmetric Allylic Alkylation

Chem. Rev. 1996, 96, 395-422 Asymmetric Transition Metal-Catalyzed Allylic Alkylations

Chem. Rev. 2003, 102, 2921-2943 Asymmetric Transition-Metal-Catalyzed Allylic Alkylations: Applications in Total Synthesis

Org. Lett., 2003, 5 1809–1812  Asymmetric Rearrangement of  Prochiral Allylic Alcohols to Chiral Allylic Amines

J. Org. Chem., 2005, 70 (2), pp 648–657 Asymmetric Synthesis of Chiral Allylic Amines

J. Am. Chem. Soc. 2009, 131, 4200-4201 Palladium-Catalyzed Allylic Amination Using Aqueous Ammonia

Org. Lett. 2008, 12, 2425-242  Synthesis of Dehydro-β-amino esters via Highly Regioselective Amination of Allylic Carbonates

J. Am. Chem. Soc. 2007, 129, 7508-7509  Iridium-Catalyzed, Asymmetric Amination of Allylic Alcohols Activated by Lewis Acids

Angew. Chem, Int Ed. 2007, 46, 3139-4143  Iridium-Catalyzed Synthesis of Primary Allylic Amines from Allylic Alcohols: Sulfamic Acid as Ammonia Equivalent

J. Org. Chem. 2009, 74, 305-311 Modular Phosphite–Oxazoline/Oxazine Ligand Library for Asymmetric Pd-Catalyzed Allylic Substitution Reactions: Scope and Limitations—Origin of Enantioselectivity

Relevant scale up example

Gram scale
Org. Process Res. Dev., 2003, 7, 432–435

5.5 Kg scale
Org. Process Res. Dev., 2012, 16, 2051–2057

Green Review

  1. Atom efficiency (by-products Mwt)
    With an optimized catalyst loading, a reasonable reaction for atom efficiency generating a salt of the leaving group. Obviously, leaving groups with as low Mwt. and with low environment impact as possible should be used – acetate is preferable to benzoate etc.
  2. Safety Concerns
    No operational safety issues or hazards apparent with this chemistry
  3. Toxicity and environmental/aquatic impact
    The biggest impact here would be the solvents employed. As with all heavy metal catalysts, contamination of the environment needs to be avoided and levels in the final API need to be controlled
  4. Cost, availability & sustainable feedstocks
    With high catalytic efficiency, this methodology can be an economical way to access complex chiral amines. All metal catalysts have a high LCI from mining and refining. Ideally, they would be recovered and recycled.
  5. Sustainable implications
    Most precious metals are at risk of depletion – Mo (medium risk of depletion) is preferred over Pd/Ir/Rh (high risk of depletion)