Interrupted SNAr-Alkylation Dearomatization

Abstract

Dearomatizations provide powerful synthetic routes to rapidly assemble substituted carbocycles and heterocycles found in a plethora of bioactive molecules. Harnessing the advantages of dearomatization typically requires vigorous reagents because of the difficulty in disrupting the stable aromatic core. A relatively mild dearomatization strategy is described that employs lithiated nitriles or isocyanides in a simple S_NAr-type addition to form σ-complexes that are trapped by alkylation. The dearomatizations are diastereoselective and efficient and rapidly install two new carbon-carbon bonds, one of which is a quaternary center, as well as nitrile, isocyanide, and cyclohexadiene functionalities.

Scheme 1. Strategies for Dearomatization

Scheme 2. Generalized Interrupted S_NAr Mechanism

Scheme 3. Scope of the Interrupted SNAr-Alkylation of Substituted Benzonitriles with Nitrile Nucleophiles

Scheme 4. Interrupted S_NAr-Alkylation Scope with Isocyanide-Containing Nucleophiles

Scheme 5. Mechanism of the Benzonitrile Dearomatization

Figure 1

Stationary points for the dearomatization of 2,6-difluorobenzonitrile by deprotonated cyclopentylcarbonitrile followed by nucleophilic substitution with p-CF₃benzyl bromide in THF at −78 °C. Free energies have been computed at the M06-2X/jun-cc-pVTZ level with the implicit SMD-PCM solvation correction. The lower potential surface is for complexes with Li⁺, where DG(Li⁺)_Cmpl is the free energy of complexation between deprotonated cyclopentylcarbonitrile and Li⁺ in THF at −78 °C. The latter energy is very difficult to estimate accurately by computational means, because of a high dependence on the solvation energy of the bare Li⁺ ion, which varies strongly with the radius assigned to Li⁺.

Figure 2

Arylnitriles evaluated with the local electron attachment energy (E_S(r)) to determine the addition regioselectivity. The asterisk marks the preferred position(s) for nucleophilic attack according to E_S(r). The figure on the right shows E_S(r) on the molecular surface of 10a. The lowest E_S(r) (red) is found at the para-position, which is also the position of the initial attack during the dearomatization. More information about the predictions of the E_S(r) calculations are found in Table S1.

Scheme 6. Mechanistic Experiments