Tag Archives: C-H activation

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.

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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.

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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.
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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.

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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.

Catalytic C–H oxidation by a triazamacrocyclic ruthenium complex

Eric McNeill and Justin Du Bois Chemical Science
DOI: 10.1039/c2sc20118f

Transition metal-catalysed methods for the chemoselective oxidation of C-H bonds have been widely developed over the past 15 years. DuBois and co-workers report a new ruthenium-based catalyst for carrying out teriary and benzylic C-H oxidations. Previous work in this area has focused on developing precatalysts that generate the active ruthenium tetroxide in situ. However, the group have taken a different approach, introducing a tridentate Me3tacn ligand to the precatalyst and generating a cis-dioxoruthenium catalytic species.

The catalyst carries out C-H oxidations selectively in a number of polyfunctional molecules at the most electron rich tertiary or benzylic C-H bond. Interestingly, the group observed that this catalytic system is more efficient than a system generating ruthenium tetroxide.

Moreover, introducing a ligand system to ruthenium-mediated oxidations raises the possibility of ligand design optimising for chemoselectivity or perhaps stereoselectivity.

Catalytic functionalization of unactivated primary C–H bonds directed by an alcohol

Eric M. Simmons and John F. Hartwig Nature

The selective incorporation of functional groups, particularly hydroxy and amino groups, into small molecules is a major challenge facing the synthetic organic chemist. Typically, methods for incorporating such groups require the interconversion of existing functionality which may require many steps rendering these transformations laborious, costly and time consuming.

Simmons and Hartwig have recently described the method for introducing β-hydroxy groups through a formal iridium catalysed C-H activation method directed by proximal silyl ethers. This strategy exploits the affinity of silicon for transition metals, in this case iridium, to direct the formation of a C-Si bond. The resulting oxasilolane was then transformed, by a Tamao-Fleming oxidation, to the corresponding 1,3-diol. For ease of isolation, the diols were finally acetylated to give the 1,3-diacetates.

The versatility of this methodology is demonstrated by converting both simple and complex alcohols into the 1,3-diol analogues.

DOI: 10.1038/nature10785