Hold them tight: Guided by X-ray structures, bifunctional thiourea catalysts containing an activating intramolecular hydrogen bond were redesigned. The new catalysts were used to effect a highly enantioselective Mannich reaction between malonates and both aliphatic and aromatic imines (see scheme; Boc=tert-butoxycarbonyl).
Catalysts
containing urea, thiourea, and tertiary amine groups
fold into a three-dimensional organized structure in solution both
in the absence as well as in the presence of substrates or substrate
analogues, as indicated by solution NMR and computational studies.
These foldamer catalysts promote Mannich reactions with both aliphatic
and aromatic imines and malonate esters. Hammett plot and secondary
kinetic isotope effects provide evidence for the C–C bond forming
event as the turnover-limiting step of the Mannich reaction. Computational
studies suggest two viable pathways for the C–C bond formation
step, differing in the activation modes of the malonate and imine
substrates. The results show that the foldamer catalysts may promote
C–C bond formation with an aliphatic substrate bearing a cyclohexyl
group by enhanced binding of the substrates by dispersion interactions,
but these interactions are largely absent with a simpler catalyst.
Additional control experiments demonstrate the ability of simple thiourea
catalysts to promote competing side reactions with aliphatic substrates,
such as reversible covalent binding of the thiourea sulfur to the
imine which deactivates the catalyst, and imine to enamine isomerization
reactions. In foldamer catalysts, the nucleophilicity of sulfur is
reduced, which prevents catalyst deactivation. The results indicate
that the improved catalytic performance of foldamer catalysts in Mannich
reactions may not be due to cooperative effects of intramolecular
hydrogen bonds but simply due to the presence of the folded structure
that provides an active site pocket, accommodating the substrate and
at the same time impeding undesirable side reactions.
ABSTRACT:Cross-dehydrogenative coupling reactions between -ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of -ketoesters and indoles. The mechanism of the reaction between a prototypical -ketoester, ethyl 2-oxocyclopentanonecarboxylate and N-methylindole, has been studied experimentally by monitoring the temporal course of the reaction by 1 H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (B97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The computational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the -keto ester ligand from an O,O'-chelate to an C-bound Pd enolate. This ligand tautomerization event is assisted by the -bound indole ligand. Subsequent scission of the '-C-H bond takes place via a proton-assisted electron transfer mechanism, where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to produce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA) 2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step.
An efficient urea-enhanced thiourea catalyst enables the enantioselective Mannich reaction between β-keto esters and N-Boc-protected imines under mild conditions and minimal catalyst loading (1-3 mol %). Aliphatic and aromatic substituents are tolerated on both reaction partners, affording the products in good enantiomeric purity. The corresponding β-amino ketones can readily be accessed via decarboxylation without loss of enantiomeric purity.
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