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 3: Silver 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.

 

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.

 

Preparation of dicationic palladium complexes for asymmetric reactions”, A. E. Sheshenev, A. M. R. Smith and K. K. Hii, Nature Protocols, 2012, 7, 1765.

doi:10.1038/nprot.2012.095

 

 

(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.

Concepts developed in the above were 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

 

Delineating origins of stereocontrol in Pd-catalyzed asymmetric a-hydroxylation of b-ketoesters, A. M. R. Smith, H. S. Rzepa, A. J. P. White, D. Billen and K. K. Hii*, J. Org. Chem., 2010, 75, 3085.

doi: 10.1021/jo1002906

(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.

An Expedient Synthesis of Olfactory Lactones by Intramolecular Hydroacylalkoxylation Reactions, L. A. Adrio and K. K. Hii, Eur. J. Org. Chem., 2011, 1852.

DOI: 10.1002/ejoc.201001556

Abstract: A series of 4,5-disubstituted γ-lactones, including whisky and cognac lactones, was synthesised in four steps from a readily available chiral precursor. By using an intramolecular hydroacylalkoxylation reaction in the final step, a correlation between the (E)/(Z) configuration of the precursor and the product distribution has been established, for the first time, in this type of cyclisation reactions.

Unusual regiodivergence in metal-catalysed intramolecular cyclisation of γ-allenols

J. L. Arbour, H. S. Rzepa, A. J. P White and K. K. Hii, Chem. Commun., 2009, 7125.

DOI: 10.1039/b913295c

Abstract: Different O-heterocycles can be obtained from a common g-allenol precursor by using Ag, Zn or Sn catalysts; the results were rationalised by molecular modelling.

Silver-catalysed enantioselective additions of O-H and N-H to allenes: a new model for stereoselectivity based on non-covalent interactions

 

J. L. Arbour, H. S. Rzepa, J. Contreras-García, L. A. Adrio, E. M. Barreiro, and K. K. Hii, Chem. Eur. J., 2012, 18, 11317.

 

DOI: 10.1002/chem.201200547

 

Abstract: The ability of silver complexes to catalyse enantioselective O-H and N-H additions to allenes is demonstrated for the first time, using optically active anionic ligands derived from oxophosphorus(V) acids as sources of chirality. Intramolecular addition of acids, alcohols and amines to allenes can be achieved with up to 73% and 68% ee, respectively. Exploitation of a CH anomeric effect allows the absolute configuration of a sample of 2-substituted tetrahydrofuran of low ee to be unambiguously assigned, by comparison of chiroptical ORD and VCD measurements with calculated spectra. In the second part of the work, the origin of stereoselectivity was probed by DFT free energy calculations of transition states. A new model of enantiomeric differentiation was developed based on non-covalent interactions, allowing us to identify the source of stereoselectivity to weak attractive interactions – these dispersive forces are often overlooked in asymmetric catalysis. A new computational approach was developed to represent these interactions as colour-coded isosurfaces, characterised by the reduced density gradient profile.