Tag Archives: JACS

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.


Uncovering alkenes: complex products from all-carbon substrates


Molecules containing simple alkene functionality are attractive substrates in synthesis. Carbon-carbon double bonds are relatively stable groups, lacking polarisation, they can be carried through synthetic processes involving acid, base, mildly oxidative and reductive conditions. But, the availability of the π-electrons for reaction embodies remarkable potential for constructing substituted contiguous stereocentres and the possibility of introducing complex functionality to an all-carbon system.

In recent years, functionalisation of unactivated alkenes has blossomed with developments in robust metal-catalysed processes and new oxidating agents. In the last few weeks several reports of new alkene functionalisations have been published that cover many aspects of this broad area, and show the diverse utility of alkenes in synthesis.

Hayashi and co-workers have published an elegant cyclising difunctionalisation of dienes.[1] The process is an iridium-catalysed C-H activation of cyclic aryl N-sulfonyl ketimines and gives spirocyclic aminoindane scaffolds with high diastereoselectivity.


We’ve already discussed an asymmetric cyclising aminofluorination reaction carried out by a chiral hypervalent iodine fluoride oxidant.[2] The reaction is endo-selective and prepares fluoropiperidine-based systems. Extension of the reaction to a racemic intermolecular process with styrene substrates was also demonstrated.


In a similar example of intermolecular alkene difunctionalisation, Zhang reports aminocyanation and diamination of (predominantly) styrene substrates.[3] The principle reagent for functionalisation is NFSI (N-fluorobenzenesulfonimide), which aminates the terminal end of the double bond. Subsequent reaction with TMSCN gives the aminonitrile product. Alternatively, an alkylnitrile may be used to give the Ritter product of the second addition.


The authors suggest a copper(I)-catalysed radical mechanism, generating a carbon-centered radical intermediate after amination by •N(SO2Ph)2. This reaction gives some idea of the kind of complex functionality that can be introduced to all-carbon alkene substrates by oxidative processes.

Hydrofunctionalisation of alkenes doesn’t provide the same high degree of complexity as oxidative difunctionalisation processes, but reactions in this category do offer a great deal of diversity in synthetic options while still providing regio- and stereocontrol of sp3 carbon centres. A report from Qing and co-workers describes a general and high yielding hydrotrifluoromethylation of unactivated alkenes.[4] Trifluoromethyl groups are useful moieties in pharmaceutical development of lead compounds. The group apply the method to a wide scope of unactivated alkene substrates showing tolerance to many other functionalities.


Hartwig’s group in Berkeley have developed an asymmetric hydroheteroarylation of bicycloalkenes.[5] The reaction is catalysed by an iridium DTBM-Segphos complex and tolerates various heteroaromatic coupling partners.


Alkenes offer chemists widely available, stable and highly tolerant substrates for synthesis. Careful application of modern reactions allows the uncovering of diverse and complex functionality from a carbon-carbon double bond, and new developments provide ever more effective methods for the preparation of desirable adducts.

1. DOI: 10.1021/ja311968d
2. DOI: 10.1002/anie.201208471
3. DOI: 10.1002/anie.201209142
4. DOI: 10.1002/anie.201208971
5. DOI: 10.1021/ja312360c

Nonenzymatic Dynamic Kinetic Resolution of Secondary Alcohols via Enantioselective Acylation: Synthetic and Mechanistic Studies

Sarah Yunmi Lee, Jaclyn M. Murphy, Atsushi Ukai, and Gregory C. Fu
J. Am. Chem. Soc


Dynamic Kinetic Resolution is a well established methodology for the stereoselective preparation of chemicals, which overcomes the low yield issue inherent in classic kinetic resolution. There are two strategies; the first one relies on the fast interconvertion of the two enantiomers of the starting material between them and the difference in relative conversion rates to the desired product (A). The second relies on the conversion of only one of the enantiomers of the product back to the starting material (B).


Although the first strategy can be implemented without the need of an enzyme, the second required atleast one enzyme – usually a deacetylase enzyme – to be successfully applied. Only recently, a non-enzymatic dynamic kinetic resolution methodology for the acylation of secondary amines, relying on the second approach has been reported. A ferrocene is used for the acylation of the substrate, whilst a ruthenium complex deacetylates only one enantiomers of the acylated product. The authors demonstrated the applicability of their method on a variety of substrates.


This non-enzymatic method is not fascinating only because the lack of an enzyme which can prove to be scare or even not compatible with the reaction conditions. It overcomes the “other enantiomer” issue. Enzymes are fantastic catalysts however they are evolved specifically to do one job and one job only, making them inherently useless for the preparation of the other enantiomer of the desired product. For non-enzymatic processes such as the one above this is not an issue. If the enantiomer of the ruthenium catalyst was used then the product obtained would have the opposite stereochemistry.

This is the first non-enzymatic dynamic kinetic resolution method for secondary alcohols reported and hopefully it will provide incentive for future development as well as inspiration for more such approaches.

Catalytic Functionalisation of Unactivated sp3 C−H Bonds via exo-Directing Groups: Synthesis of Chemically Differentiated 1,2-Diols

Zhi Ren, Fanyang Mo, and Guangbin Dong
J. Am. Chem. Soc.
DOI: 10.1021/ja3082186

Selective C-H oxidation of unactivated alkyl groups is a remarkably powerful way of installing new functionality in simple substrates. We’ve featured some developments in this area previously.

C-H oxidation at the β-carbon of an unactivated alcohol has, so far, been inaccessible due to the deactivating inductive effect of the proximal oxygen. Dong and co-workers have overcome this problem in a method that allows the selective preparation of orthogonally protected 1,2-diols from simple alcohol precursors.

Their method employs a neat oxime derivative of the alcohol to direct palladium C-H insertion β to oxygen. Oximes are known to direct palladation of C-H bonds on the ‘other side’ of the oxime moiety; by removing appropriate C-H bonds from the oxime directing group, palladation in this case occurs on the desired oxygen ‘side’.

The authors note that reaction concentration is critical to the success of the oxidation process. The optimised process uses a concentration of 0.2 M. At lower concentration (0.1 M) the reaction does not go to completion; at higher concentration (0.4 M) decomposition products are observed. Whether or not this narrow range of optimal conditions is variable by substrate is not discussed, but the scope of the reaction is exemplified in a number of substrates with consistently good conversion.

Selective preparation of 1,2 diol derivatives is critical to any application of this methodology in synthesis. The oxime directing group can be removed as a protecting group in the presence of the adjacent acetate. Similarly, the oxime is stable under conditions for acetate cleavage, allowing selective differentiation between the two masked hydroxyl groups.

Interestingly, the reaction gives better yields on larger scale. A test example showed an improvement from 61% yield on 0.1 mmol scale to 80% yield from a 5 mmol reaction.

In one example, a substrate derived from menthol was subjected to the reaction conditions. Instead of observing the expected 1,2 oxidation product, a postulated intermediate undergoes an interesting skeletal rearrangement to give an unusual substituted cyclopentane scaffold.

Highly Diastereo- and Enantioselective Cu-Catalyzed [3 + 3] Cycloaddition of Propargyl Esters with Cyclic Enamines toward Chiral Bicyclo[n.3.1] Frameworks

Cheng Zhang, Xin-Hu Hu, Ya-Hui Wang, Zhuo Zheng, Jie Xu, and Xiang-Ping Hu
J. Am. Chem. Soc.
DOI: 10.1021/ja303129s

Bridged bicyclic structures are common motifs in many naturally occurring and bioactive compounds. As such, these systems are attractive targets for synthetic chemists. However, their highly shape-defined structure poses an interesting synthetic challenge. Common approaches in preparation of bridged systems include regiospecific Heck couplings and carbenoid addition-Claisen rearrangement cascades.

These approaches, although reliable, are characterized by long syntheses of the cyclization substrates.

A group from the Chinese Academy of Sciences in Beijing has recently reported a diastereo- and enantio-selective Cu(II)-catalysed formal [3+3] cycloaddition for the preparation of bicyclo(n.3.1) structures from simple propargyl esters and cyclic enamines. Treatment of the propargyl ester with Cu(OAc)2 in the presence of a chiral tridentate ligand yield a very reactive allenylidene intermediate, which undergoes cycloaddition in the presence of an enamine nucleophile.

The reaction is shown to work best with six membered cyclic enamines, which can also contain heteroatoms. However, decent yields were also obtained with five and seven membered nucleophiles.

The bicyclo(n.3.1) products can be functionalised stereoselectively either through C-C double bond chemistry or carbonyl chemistry and serve as building blocks for the synthesis of more complicated systems.

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.

“Silver Effect” in Gold(I) Catalysis: An Overlooked Important Factor

Dawei Wang, Rong Cai, Sripadh Sharma, James Jirak, Sravan K. Thummanapelli, Novruz G. Akhmedov, Hui Zhang, Xingbo Liu, Jeffrey L. Petersen, and Xiaodong Shi
J. Am. Chem. Soc.
DOI: 10.1021/ja303862z

Occasionally the topic of trace palladium catalysis in processes reported to be iron catalysed appears in the literature and, more often, in questions asked in seminars on iron catalysis. The trace palladium in these cases can come from reaction flasks than haven’t been properly cleaned or from impurities in the metal that’s added. In gold catalysis, a silver salt with a non-coordinating counter ion (eg. SbF6-) is often added to abstract a halogen from the gold species, leaving the homogenous gold catalytic system and notoriously insoluble silver halides, which can be removed by filtration. However, often the precipitate is simply left in the reaction flask in the assumption that it won’t participate in the reaction. But does it?

A study from the Shi group in West Virginia begins to answer this question in an impressively thorough manner. Their initial interest began when a report in the literature contradicted work going on in the group. Further investigation showed that if the gold catalyst was filtered through Celite to remove silver salts, then no activity was observed. But, if it was not filtered or filtered using only filter paper, then the catalytic system retained activity. X-ray photoelectron spectroscopy was employed to determine the metal composition of the two filtrates and showed that filter paper wasn’t sufficient to remove all the silver, suggesting a cooperative catalytic system. Phosphorus NMR studies also revealed that the gold complexes in solution were influenced by silver, promoting catalytic activity.

Having solved the original issue, the group commendably set about investigating a wide range of gold catalysed reactions reported in the literature and the “silver effect” on the reactivity of the catalytic systems. They divided the reactions into 3 categories;

  • Type 1 – True [L-Au]+ Catalysis

  • Type 2 – Bi-Metallic Catalysis – Requires Au/Ag mixture

  • Type 3 – Silver Assisted Catalysis – Variable reactivity with Au, Ag or Au/Ag mixture

Of the 14 literature reactions tested only 2 were found to be true gold catalysis with the silver content of the system having no effect on activity. Five examples were shown to be Type 2 – requiring both gold and silver to be present for reaction. Indeed, if the catalyst was activated and then filtered through Celite to remove any silver traces, the catalysts were inactive, but the addition of “insoluble” silver chloride, which cannot activate gold by halide abstraction, formed a catalytically active system. The majority of the remaining reactions were Type 3; pure gold systems could catalyse the reactions but the presence of silver increased catalytic activity. Two reactions which were broadly classed as type 3 were equally as good with gold, silver or a mixture.

This work potentially opens up new areas in gold-silver bimetallic catalysis and certainly highlights the importance of thorough investigation in the development of gold-catalysed reactions.