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Transition Metal Catalysed C-H Activation

Transition metal catalysis lies at the heart of modern innovative science. As the field has matured, new areas have emerged that challenge the frontiers of synthetic organic chemistry. The capacity to activate a specific 'inert' C-H bond and transform it to a more versatile functional group is an emerging area in chemistry. To expand this area in organic synthesis, the challenge is to identify novel strategies for the formation of organo-metal intermediates under mild conditions and to discover new methods for their subsequent functionalisation. This process is perhaps the ultimate synthetic transformation and presents an exciting and fundamental challenge for chemists.

We are interested in developing new inter- and intramolecular C-C bond forming reactions catalysed by transition metals. In particular, our research focuses on the activation of C-H bonds and we are investigating methods by which sp, sp2 and sp3 hybridised C-H bonds can be activated by transition metal catalysts under ambient conditions to form a diverse range of useful molecular architectures.

C-H Activation and Functionalisation; Target Structures for C-H Activation

We are targeting a number of functional groups that we believe are capable of selective C-H activation and developing novel coupling strategies that involve tandem carbon-carbon bond formation processes, stereoinduction and complexity generating reactions.

Functional Groups for C-H Activation

In order to efficiently identify potential new processes we adopt parallel screening techniques that enable us to perform and monitor many reactions simultaneously. Thus, the discovery and development process can be accelerated leading more rapidly to an new optimised transformation.


A rapid method for reaction discovery and optimisation

C-H activation is at the cutting edge of synthetic organic chemistry. It allows the chemist to perform the unexpected disconnection and enables innovative and imaginative synthetic strategies.

Intermolecular Palladium-Catalysed Alkenylation of Indoles via Solvent-Controlled Regioselective C-H Functionalization

Over the past three decades the Heck reaction has become one of the most fundamental metal catalysed C-C bond forming processes for the synthesis of complex molecules. Despite its huge impact on the synthetic community the overall coupling of the two fragments requires two discrete activation steps: 1) formation of an aryl or vinyl halide and 2) the palladium(0)-catalysed union of the reaction partners (eqn. 1). While this reaction represents a cornerstone in synthetic chemistry, a direct oxidative Heck reaction would bypass the need for pre-activated reaction partners and lead to a more efficient process. Towards this, Fujiwara and Moritani developed an efficient coupling of arenes and activated alkenes via an oxidative palladium(II)-catalyzed process and this transformation has found widespread use in synthesis (eqn. 2).

The catalytic functionalisation of aromatic heterocycles is an important transformation for the synthetic chemist, and in particular, methods for the synthesis and elaboration of indoles have received significant attention. The indole motif is a ubiquitous feature of alkaloid and peptide natural products and represents an important structure for the pharmaceutical industry. Surprisingly, the development of an oxidative C-3 alkenylation of free (NH)-indoles has received little attention and to the best of our knowledge there is no example of a C-2 intermolecular oxidative alkenylation of the free (NH) indole nucleus. We have developed a general direct oxidative Heck reaction that exploits a novel, selective, solvent-controlled palladium-catalysed C-H functionalization of free (NH)-indoles leading to the elaboration of the heteroaromatic nucleus at either the C-2 or C-3 position (eqn. 3).

Heck, oxidative Heck, C-H transformations of indoles

The natural reactivity of indole suggested that palladation and Heck coupling would take place preferentially at the C-3 position. However, we speculated that it might be possible to control the selectivity of the reaction by the use of different solvents and additives. Fundamental to this hypothesis was the knowledge that the migration of groups from the C-3 to C-2 position of indole has been observed in the alkylation of 3-substituted indoles (Scheme 1). By analogy, we anticipated that a migration of the C3-PdX bond to the C-2 position would enable a complementary C-H functionalization process that would be a valuable transformation for synthetic chemists.

While at this stage we cannot be certain of the mechanism we propose a plausible pathway for the two reactions in Scheme 2. C-3 Palladation is thought to occur via intermediate I, and following re-aromatization to II a Heck-type reaction forms the C-3 derived indole, 3. Under neutral conditions, the acetate ion formed from the attack of indole on Pd(OAc)2 will readily remove a proton from I to form C-3 palladated species II. In contrast, under acidic reaction conditions we propose that this deprotonation would be slowed. This could allow a migration of the C3-PdX bond in I to the highly activated iminium C-2 position giving intermediate III and ultimately IV. The effect of the co-solvent as well as the presence of AcOH is also important since the results in Table 1 suggest that strongly coordinating solvents (DMSO, MeCN) override any effect from the presence of acid, leading to C-3 selectivity. However, with weakly coordinating 1,4-dioxane as a solvent the proposed migration is still seemingly facile, even without addition of acid, leading to C-2 derived indole, 2, as the major isomer. It is also possible that the C-3 palladation is reversible leading ultimately to C-2 palladation prior to coupling. This requires the C-2 palladated species to be both thermodynamically more stable and the rate of insertion to the alkene to be slow. Mechanistic investigations are currently underway and these results will be reported in due course.

Indole catalytic cycle

A range of indoles and alkenes participate in the regioselective oxidative coupling reaction. Importantly, free (NH)-indoles are suitable substrates for this process.


Indole summary

It was also possible to further derivatize the indole products via C-H functionalisation thus providing access to highly functionalised indoles via catalytic methods. This strategy allows the selective installation of substituents to either position in any order.

In summary, we have developed a general method for the selective intermolecular alkenylation of indoles via a palladium-catalysed C-H functionalisation reaction. The nature of the solvent is crucial in controlling the regioselectivity of the reaction and as a result the alkenylation can be directed to either the C-2 or C-3 position of free (NH)-indoles. This discovery could have important consequences for the selective elaboration of other heteroaromatic nuclei. Current efforts are directed towards improving the efficiency and scope, a more detailed mechanistic investigation, and application to other heteroaromatic nuclei.

Reference

  1. Angew. Chem. Int. Ed. 2005, 44, 3125
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