HFIP Mediates a Direct C-C Coupling between Michael Acceptors and Eschenmoser's salt

Abstract

A direct C-C coupling process that merges Michael acceptors and Eschenmoser's salt is presented. Although reminiscent of the Morita-Baylis-Hillman reaction, this process requires no Lewis base catalyst. The underlying mechanism was unveiled by a combination of kinetic, isotopic labelling experiments as well as computational investigations, which showcased the critical role of HFIP as a superior mediator for proton-transfer events as well as the decisive role of the halide counterion.

Keywords: Amines; Hydrogen bonds; Iodine; Quantum chemistry; Solvent effects.

Scheme 1

a) The Morita–Baylis–Hillman reaction. b) A catalyst‐free variant relying on Eschenmoser's salt and HFIP.

Scheme 2

a) Solvolysis of Eschenmoser's and Böhme's salt in HFIP at the optimised concentration and the computed relative Gibbs free energies for the dissociation event. b) DFT‐optimized structures of the (CH₃)₂NCH₂X*3HFIP molecular clusters found through the use of extensive metadynamic sampling.

Scheme 3

Reaction scope of the MBH‐type coupling of Michael acceptors and Eschenmoser's salt. The reaction was carried out on a 0.2 mmol scale; a) 79 % NMR yield, b) 84 % NMR yield, c) reaction conducted at room temperature, d) 75 % NMR yield, e) 4 equiv Eschenmoser's salt were used.

Scheme 4

Experimental observations regarding the mechanism.

Scheme 5

Proposed mechanism (a) and computed relative Gibbs free energy profiles (b)–(e) in the proton‐transfer steps for HFIP (green) and iPrOH (brown). The relative free energies are presented in kcal mol⁻¹ for each proton‐transfer step individually having the respective reactant complex as a reference (0.0 kcal mol⁻¹).

Scheme 6

Derivatisation of aza‐MBH products. a) A [2,3]‐Stevens‐type alkylation/rearrangement cascade. b) A direct synthesis of zwitterionic amino acids. 7a_CCDC_2079100; 7c_CCDC_2079101; 7d_CCDC 2079099.