Preparation of sec and tert amines by Buchwald-Hartwig Amination

Mechanism + Description

The B-H amination follows the usual pathway of oxidative insertion of a Pd⁽⁰⁾ catalyst into an aryl halide/sulfonate followed by coordination of the amine followed by reductive elimination to give the product. If a Pd⁽²⁺⁾ salt/complex is added, pre-reduction to the active Pd⁽⁰⁾ catalyst is needed. The role of the base is to deprotonate the amine prior to, or after coordination to the Pd catalyst.

General comments

Typically the reagents are mixed with a Pd complex or a mixture of a simple Pd salt/complex and added ligands to generate the active catalyst in situ. The Pd can be added as Pd⁽²⁺⁾ –usually Pd(OAc)₂– or Pd ⁽⁰⁾ –usually Pd_x(DBA)_y. Traditional ligands for the B-H amination reaction are are Ph₃P and (o-Tolyl)₃P, although since first published the B-H amination has been reported with a wide range of other ligands – principally phosphines and stabilised carbenes – which have been developed to fine tune catalytic activity and allow reaction with traditionally difficult or unreactive coupling partners like aryl chlorides and very electron rich aryl / hetero-aryl bromides. Correct choice of ligand can also minimise reductive dehalogenation of the aryl halide coupling partner. Phosphine ligands cover mono and bidentate as well as very sterically hindered ligands. In many cases, phosphine ligands developed for other transformations like chiral hydrogenation are used in B-H amination reactions, and occasionally chiral ligands are used when there is no chiral demand in the product. Bases  are typically inorganics like NaOH, Na/K/Cs₂CO₃, Na/KHCO₃ and K_XH_YPO₄ or alkoxides – Na/K t-BuO. Occasionally organic amine bases are employed.

Key references

Chem Sci., 2011; 2(1): 27–50 DialkylbiarylPhosphines in Pd-Catalyzed Amination: A User’s Guide

J. Org. Chem., 2014, 79, 11961–11969 Role of the Base in Buchwald–Hartwig Amination

Recent Advances in the Buchwald–Hartwig Amination Reaction Enabled by the Application of Sterically Demanding Phosphine Ancillary Ligands

J. Am. Chem. Soc., 2012, 134,  700–706 Completely N1-Selective Palladium-Catalyzed Arylation of Unsymmetric Imidazoles: Application to the Synthesis of Nilotinib

J. Am. Chem. Soc., 2008, 130,  6686–6687 A New Class of Easily Activated Palladium Precatalysts for Facile C−N Cross-Coupling Reactions and the Low Temperature Oxidative Addition of Aryl Chlorides

Angew. Chem. Int. Ed., 2002, 41, 4746-4748 Unparalleled Rates for the Activation of Aryl Chlorides and Bromides: Coupling with Amines and Boronic Acids in Minutes at Room Temperature

Org. Process Res. Dev., 2006, 10, 762-769 Effect of Solvents on the Product Distribution and Reaction Rate of a Buchwald-Hartwig Amination Reaction

J. Am. Chem. Soc., 2008, 130, 13552–13554 A Highly Active Catalyst for Pd-Catalyzed Amination Reactions: Cross-Coupling Reactions Using Aryl Mesylates and the Highly Selective Monoarylation of Primary Amines Using Aryl Chlorides

Org. Lett., 2008, 10, 3505–3508 Water-Mediated Catalyst Preactivation: An Efficient Protocol for C−N Cross-Coupling Reactions

Chem. Eur. J., 2006, 12, 5142–5148 Rapid Room Temperature Buchwald–Hartwig and Suzuki–Miyaura Couplings of Heteroaromatic Compounds Employing Low Catalyst Loadings

J. Am. Chem. Soc., 2003, 125,  13978–13980 Insights into the Origin of High Activity and Stability of Catalysts Derived from Bulky, Electron-Rich MonophosphinobiarylLigands in the Pd-Catalyzed C−N Bond Formation

Org. Process Res. Dev., 2014, 18, 180−190 Carbon−Heteroatom Coupling Using Pd-PEPPSI Complexes

Org. Process Res. Dev., 2007, 11, 956–965 Applicability of a Fiber-Supported Catalyst on a Buchwald–Hartwig Amination

Org. Lett., 2011, 13, 5540–5543 An Efficient and General Method for the Heck and Buchwald–Hartwig Coupling Reactions of Aryl Chlorides

J. Am. Chem. Soc., 2008, 130, 6686–6687 A New Class of Easily Activated Palladium Precatalysts for Facile C–N Cross-Coupling Reactions and Low Temperature Oxidative Addition of Aryl Chlorides

Organometallics, 2003, 22, 987–999 High-Activity Catalysts for Suzuki Coupling and Amination Reactions with Deactivated Aryl Chloride Substrates:  Importance of the Palladium Source

Relevant scale up examples with Scheme

Org. Process Res. Dev., 2008, 12, 512–521
Experimental
Multi- kg scale

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

Org. Process Res. Dev., 2015, 19 (3), 476–485
Experimental
8 kg scale

Org. Process Res. Dev., 2004, 8, 925-930
Experimental
40 kg scale

Org. Process Res. Dev., 2006, 10, 472-480
Experimental
4 kg scale

Org. Process Res. Dev., 2010, 14, 849–858
Experimental
3.5 kg scale

Org. Process Res. Dev., 2014, 18 (12), 1752–1758
Experimental
250 g scale

Org. Process Res. Dev., 2012, 16, 70–81
Experimental
83 kg scale

Org. Process Res. Dev., 2013, 17, 672−678
Experimental
50 g scale