Heterofunctionalisation of C=C & C-H Bonds

With greater awareness of sustainability of industrial processes and their impact on the environment, the development of atom-efficient and selective catalysts has become an important area of research. Functionalisation of C=C or C-H bonds is highly atom-efficient, and generates valuable materials from cheap precursors. With many cases, the reactions poses additional challenges in stereoselectivity. We have been developing new catalysts that can be used to facilitate the heterofunctionalisation of C=C and (lately) C-H moieties:

 

Project 1: Palladium catalysis

Project 2: Copper Catalysis

Project 1. Palladium Catalysts

Palladium-Catalysed Addition of R2NH to Double Bonds. Synthesis of alpha-Amino Tetrahydro-Furan and Pyran Rings, X. H. Cheng and K. K. Hii, Tetrahedron, 2001, 57, 5445.

doi:10.1016/S0040-4020(01)00446-X 

Abstract: Efficient addition of R1R2NH to unsaturated heterocycles has been achieved using palladium catalysts. The methodology was applied to the synthesis of a number of α-amino tetrahydrofurans and pyrans. Nature of amine, ring size and catalyst were found to affect the reaction. Mechanistic aspects of the reactions were explored by deuterium labelling experiments.

 

Air- and Moisture- Stable Cationic (Diphosphine)palladium(II) Complexes as Hydroamination Catalysts. X-ray Crystal Structures of Two [(diphosphine)Pd(NCMe)(OH2)]2+[OTf]-2 Complexes, K. Li, P. N. Horton, M. B. Hursthouse and K. K. Hii, J. Organometallic Chem., 2003, 665, 250.

doi:10.1016/S0022-328X(02)02138-1

Abstract: A series of cationic (diphosphine)palladium(II) complexes have been prepared and fully characterized, including two crystal structures. These complexes were evaluated as catalysts for the hydroamination of acyclic alkenes. The reactivity of the catalysts is dependent on the ligand and the substituents on the amine and alkene substrates.

 

Dicationic [(BINAP)Pd(solvent)2]2+[TfO]-2: Enantioselective Hydroamination Catalyst for Alkenoyl-N-Oxazolidinones, K. Li and K. K. Hii*, Chem. Commun., 2003, 1132 (Top 10 most accessed article for May 2003).

doi:10.1039/b302246c

Abstract: Dicationic (BINAP)palladium(II) complex induced high enantioselectiviies in the addition of primary (and secondary) aromatic amines to a, b-unsaturated oxazolidinones (up to 93% ee).

 

Asymmetric Synthesis of b-Amino Acid and Amide Derivatives via Catalytic Conjugate Addition of Aromatic Amines to N-Alkenoyl Carbamates, K. Li, X. Cheng and K. K. Hii, Eur. J. Org. Chem., 2004, 959 (Most frequently downloaded Short Communications 2004).

doi:10.1002/ejoc.200300740

Abstract: We report a highly active palladium catalyst for the enantioselective conjugate addition of primary aromatic amines to N-alkenoylcarbamates, furnishing b-amino N-Boc-amides in extremely high yields (>99 %) and unprecedented optical purity (>99 % ee) with just 2 mol % catalyst loading.

 

Enabling Ligand Screening for Pd-catalysed Enantioselective aza-Michael Addition Reactions, P. H. Phua, J. G. de Vries and K. K. Hii, Adv. Synth. Catal., 2006, 348, 587.

doi:10.1002/adsc.200505404 

Abstract: The bis(trifluoromethanesulfonate)palladium(II) dihydrate complex, Pd(OTf)2.2H2O, is an active palladium(II) precursor for the generation of dicationic palladium(II) catalysts. Parallel ligand screening is enabled for the first time, and twenty-four chiral ligands were evaluated for the asymmetric aza-Michael addition of aromatic amines to a, b-unsaturated N-alkenoylimides and carbamates. Enantioselectivities of >99% can be obtained. Catalytic precursors have been identified. doi:

 

Elucidating the Mechanism of the Asymmetric aza-Michael Reaction, P. H. Phua, S. P. Mathew, A. J. P. White, J. G. de Vries, D. G. Blackmond and K. K. Hii, Chem. Eur. J., 2007, 13, 4602.

doi: 10.1002/chem.200601706  

Abstract: The mechanism of the palladium-catalysed asymmetric aza-Michael addition of aniline to a, b-unsaturated N-imide was examined from several aspects using a combination of techniques, including X-ray crystallography, mass spectrometry, NMR, UV/Vis spectroscopy, and kinetic studies. The study culminated in the design of a new reaction protocol. By maintaining a low concentration of the aniline substrate during the course of the reaction, significant enhancement of yield and enantioselectivity can be achieved.

 

 

 

(a) Addition of amines to dihydrofuran and dihydropyran

(c) Asymmetric a-hydroxylation of 1,3-ketoesters

(a) Addition of O-H to norbornene

Copper(II)-catalysed Addition of O-H Bonds to Norbornene, J. G. Taylor, N. Whittall and K. K. Hii, Chem. Commun., 2005, 5103.

doi:10.1039/b509933a

Abstract: Cu(OTf)2 is an inexpensive, air- and moisture-stable catalysts for the O-H addition of aliphatic and aromatic acids and alcohols to norbornene.

(b) Addition of sulfonamides and carbamates to conjugated dienes

Copper Catalyzed Intermolecular Hydroamination of Alkenes, J. G. Taylor, N. Whittall and K. K. Hii, Org. Lett., 2006, 8, 3561.

doi:10.1021/ol061355b

Abstract: Regioselective additions of arylsulfonamides to vinylarenes, norbornene, and cyclohexadiene were achieved using a copper-diphosphine catalyst under mild reaction conditions. These processes appear to be ligand-accelerated.

(c) Addition of phenols to 1,3-dienes

A Recyclable Copper(II) Catalyst for the Annulation of Phenols with 1,3-Dienes, L. A. Adrio and K. K. Hii, Chem. Commun., 2008, 2325.

doi:10.1039/b719465j

Abstract: Air- and moisture-stable Cu(OTf)2–bipy catalyses the addition of phenols to 1,3-dienes under aerobic conditions in a tandem hydroalkoxylationrearrangementhydroalkylation sequence, furnishing O-heterocycles in moderate to good yields, and can be recycled without any loss in catalytic activity.

The concepts developed in the above was extended to the heterofunctionalisation of the acidic C-H present in 1,3-ketoesters. Using dicationic Pd(II) as a catalyst, very high ee's (up to 98%) can be achieve in the a-hydroxylation of 1,3-ketoesters

Palladium-Catalysed Enantioselective a-Hydroxylation of b-Ketoesters, A. M. R. Smith, D. Billen and K. K. Hii*, Chem. Commun., 2009, 3925.

doi: 10.1039/b907151b

(b) Asymmetric hydroamination/Aza-Michael reactions

(d) Intramolecular cyclisation of w-alkenols and alkenoic acids

Copper-Catalysed Intramolecular O-H addition to Unactivated Alkenes, L. A. Adrio, L. S. Quek, J. G. Taylor and K. K. Hii, Tetrahedron, 2009, 65, 10334.

doi:10.1016/j.tet.2009.10.055

Abstract: Intramolecular cyclization of w-alkenoic acids and alkenols can be achieved using a catalytic amount of Cu(OTf)2 to afford lactones and cyclic ethers, offering a practical alternative to existing catalysts.