Synthesis of Primary Amines / Hydrazines via Buchwald-Hartwig Amination

Mechanism + Description

Mechanism as for Pd catalysed B-H amination for secondary and tertiary amines.


General comments

Primary amines can be constructed using B-H amination methodology. Initially, ammonia equivalents like HN(TMS)2 or benzophenone imine were used followed by deprotection to reveal the primary amine. Catalyst systems have now been identified that work with NH3 directly thus making this transformation more mass efficient.  Likewise, aryl/heteroaryl hydrazines can be prepared from benzophenone hydrazone, or with certain ligands, N2H4 directly.


Key references

Chem. Eur. J., 2013, 19, 16760–16771 BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides

J. Org. Chem., 2008, 73, 8880-8892 Use of HN(TMS)2 as an NH3synthon in Buchwald-Hartwig amination

Tet. Lett., 1997, 38, 6367–6370 An Ammonia Equivalent for the Palladium-Catalyzed Amination of Aryl Halides and Triflates

Chem. Soc. Rev., 2010, 39, 4130-4145 Direct amination of aryl halides with ammonia

J. Am. Chem. Soc., 2009, 131, 11049–11061 Palladium-Catalyzed Coupling of Ammonia with Aryl Chlorides, Bromides, Iodides, and Sulfonates: A General Method for the Preparation of Primary Arylamines


Relevant scale up examples with Scheme

Org. Process Res. Dev., 2006, 10, 70-77
7 kg scale

Org. Process Res. Dev., 2014, 18 (12), 1752–1758
1 kg scale

Org. Process Res. Dev., 2008, 12, 512–521
8 kg scale

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