Tag Archives: Organocatalysis

Organotextile catalysis

Ji-Woong Lee, Thomas Mayer-Gall, Klaus Opwis, Choong Eui Song, Jochen Stefan Gutmann, and Benjamin List
DOI: 10.1126/science.1242196


I’ve written a research highlight for Nature Chemistry talking about Opwis’ and List’s recent paper on organotextile catalysis in Science. Take a look.

Catalytic cloth

Image credit: © 2013 American Association for the Advancement of Science

Organocatalytic C−H Bond Arylation of Aldehydes to Bis-heteroaryl Ketones

Qiao Yan Toh, Andrew McNally, Silvia Vera, Nico Erdmann and Matthew Gaunt
J. Am. Chem. Soc.
DOI: 10.1021/ja400051d

The synthesis of ketones bearing a diverse range of aryl and heteroaryl functionality is of great importance to the medicinal chemistry industry as they can be readily converted into structural motifs commonly found in medicinal agents.


A novel approach to these scaffolds has been developed by Gaunt et al who exploit the inherent electrophilicity of diaryliodonium salts by using them to trap carbogenic nucleophiles to form carbon–aryl bonds. The driving force for this research is the lack of known methods for the preparation of bis-heteroaryl ketones. The authors set themselves the challenge of developing an organocatalytic method for the regioselective diaryl ketone formation which is tolerant of a broad range of hetreoaromatic nuclei derived from diaryliodonium salts and carbogenic nucleophiles. This was achieved by using a commercially available NHC-organocatalyst with DMAP as the base to form a nucleophilic enolate from the heteroaromatic aldehyde substrate. Subsequent trapping of this enolate by the heteroaryl iodonium salt gave the bis-heteroaryl ketone products in up to 91% isolated yield.


The broad scope of this transformation was illustrated with a variety of aryl and heteroaryl aldehydes. More interestingly, however, Gaunt and co-workers have shown that the use of a non-symmetrical diaryliodonium salts is tolerated in excellent selectivity.

Non-symmetrical diaryliodonium salts are more economical as they are prepared with only one equivalent of the transferring group. Out of a number of non-symmetrical diaryliodonium salts screened, a uracil-pyridine salt displayed the best selectivity with the desired bis-heteroaryl ketone isolated with no evidence of the undesired ketone identifiable in the crude 1H NMR.

Finally, to further illustrate the utility of this methodology, the Gaunt research team demonstrated that a bis-heteroaryl ketone could be readily converted into enantioenriched amines by an Ellman imine formation and subsequent reaction with methylmagnesium bromide to give an α-tertiary amine in high yield and enantiopurity after cleavage of the chiral auxiliary.


“Black Swan Events” in Organic Synthesis

William Nugent
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201202348

The moral of this article can be summarised in three words of folk wisdom: never say never. This article provides a refreshing insight into the misplaced preconceptions of chemists working in previous decades, and how these preconceptions were overturned.

The author lays out a series of dogmatic statements which over the past two decades have been proven incorrect. These statements are classed into two categories depending whether they were brought down by a single publication – “Change through revolution”, or a series of reports – “Change through evolution”.

A selected few are:

“Gold compounds are simply to unreactive to be useful as homogeneous catalysts”

A report by Teles et al. in 1998 demonstrated that a cationic Au(I) complex catalyses the addition of oxygen nucleophiles to acetylenes:

“Olefin metathesis is an ill-defined reaction of olefinic hydrocarbons and unlikely to find any use in organic synthesis”

For students studying organic synthesis today, it’s hard to imagine a time before ubiquitous olefin metathesis, more so that it was considered so far out of reach. R.H. Grubbs ultimately shared the Nobel Prize in Chemistry in 2005 for his research on ruthenium catalysed olefin metathesis.

“Efficient enantioselective catalysis requires the use of a metal complex”

And then came one of the most elegant and sophisticated aspects of catalysis in organic synthesis: organocatalysis, with the work of MacMillan, List, Barbas and others.

As the author points out, a common characteristic of the above overruled statements is that often, the scientific literature contained hints that the “common belief” was incorrect. However, these hints were not picked up on until a report was published proving that the original discounted phenomenon was in fact achievable.

The discovery of something completely new and revolutionary is often preceded by flashes of insights or moments of wisdom that will most probably be ignored until three or four decades later when someone has the curiosity to move it forwards.

So what assumptions about the behavior of molecules do we make today that will populate a surrogate of this article in 50 years?

Enantioselective α-Vinylation of Aldehydes via the Synergistic Combination of Copper and Amine Catalysis

Eduardas Skucas and David W. C. MacMillan
J. Am. Chem. Soc.
DOI: 10.1021/ja303116v

The stereoselective preparation of α-vinyl carbonyl compounds is a challenging task for synthetic chemists mainly due to their tendency to racemize under reaction conditions. MacMillan and Skucas report a multicatalysis protocol for the enantioselective α-vinylation of aldehydes under very mild conditions. Using vinyl iodonium triflate species as starting materials, an imidazolidinone organocatalyst to induce stereoselectivity, and a Cu(I) salt, they have devised an efficient and useful synthetic tool for the enantioselective preparation of β,γ-unsaturated aldehydes.

They propose that the Cu(I) catalyst undergoes an oxidative addition to the vinyl iodonium triflate substrate to form a highly electrophilic Cu(III) vinyl complex. At the same time, the imidazolidinone organocatalyst reacts with the aldehyde substrate to form the corresponding enamine. Complexation of the enamine with the Cu(III) species and subsequent reductive ellimination liberates the Cu(I) metal completing one of the catalytic cycles. Hydrolysis of the resulting imminium species yields the desired α-vinyl aldehyde and the imidazolidinone organocatalyst completing the second catalstic cycle.

The authors also investigated the scope of the reaction for both the aldehyde and vinyl coupling partners demonstrating that the protocol can tolerate sterically demanding β-branched aldehydes, protected heteroatoms, electron-poor styrenes as well as trisubstituted carbocycles. The stereochemical induction has been demonstrated to be completely under control of the organocatalyst as preexisting stereocentres do not influence the stereochemical outcome.

Utilising routine reactions, α-vinyl aldehydes can be transformed into a variety of compounds and used as versatile precursors for the synthesis of larger molecules.

A Redox-Reconfigurable, Ambidextrous Asymmetric Catalyst

Shahab Mortezaei, Noelle R. Catarineu, and James W. Canary J. Am. Chem. Soc.
DOI: 10.1021/ja302283s

Various new catalysis paradigms are being developed in modern chemistry, such as cooperative catalysis, cascade catalysis or proximity catalysis. However, new work presented by Canary and co-workers features a new concept: templating of organocatalytic ligands by a metal centre, generating a rigid, chiral complex capable of carrying out asymmetric catalysis. The most remarkable feature of this catalytic complex is the ability to switch the enantioselectivity of the catalyst by altering the oxidation state of the metal.

Previous work from the group has revealed a copper ligand complex that switches ‘handedness’ of pseudo-helical ligand conformation upon one electron transfer to or from the metal centre; alternating between Cu(II) (right handed) and Cu(I) (left handed). The ligands are based on L-methioninol and the handedness of the structures is derived from the differing affinity of the copper for O– and S-ligands in different oxidation states.

In this piece of work, the ligands are further functionalised with organocatalytic urea moieties. The group show the ligand to be competent in catalysing the Michael addition of malonate to a nitroalkene in the absence of the copper. Without copper there is no selectivity, but complexes of the ligand with either Cu(I) or Cu(II) result in clear selectivity for R or S respectively.

When the Cu(II) catalyst is used in the reaction, isolated, reduced with ascorbate to Cu(I) and resubmitted to reaction conditions the yields and ee are consistent but the selectivity reversed. Whilst neither the yields nor selectivities are outstanding as yet, the concept opens new possibilities for developments in tuneable catalysis.

A Catalytic Tethering Strategy: Simple Aldehydes Catalyze Intermolecular Alkene Hydroaminations

Melissa J. MacDonald, Derek J. Schipper, Peter J. Ng, Joseph Moran and Andre M. Beauchemin J. Am. Chem. Soc.

Broadly speaking, synthetic catalysis operates by activating a reacting partner by lowering the LUMO in electrophiles or (less commonly) raising the HOMO in nucleophiles in order to reduce the energy of activation required for reaction. Recent advances in catalysis have developed systems for activating both reaction partners.

However, as well as substrate activation, catalysts often perform another crucial role in reaction pathways: substrate preorganisation. Asymmetric catalysis relies heavily on the ability of the catalyst to organise at least one of the reacting partners into a specific conformation. And proximity effects allow for highly chemoselective transformations, used heavily in C-H activation techniques.

While it is common for a catalyst system to carry out substrate activation without any degree of substrate preorganisation, there are hardly any reported systems where a catalyst brings substrates together without activating either species for reaction.

Beauchemin reports conditions for carrying out hydroaminations with hydroxy amines (reverse Cope elimination) using an aldehyde as catalyst to bring the two reaction partners together temporarily. The technique relies on the reversible formation of a mixed aminal intermediate where hydroamination can take place in an intramolecular fashion.

Their studies found that benzyloxyacetaldehyde works efficiently as catalyst in 20 mol% loading, and a series of diamines were prepared. The authors also show that chiral aldehydes can induce asymmetry in the reaction.

The concept of temporary intramolecularity may be applicable to other reactions, but a complex balance of kinetics involving the equilibria between iminiums, all possible aminals and the relative rates of reaction, both inter- and intramolecularly, needs to be achieved in any prospective system.

DOI: 10.1021/ja208867g