α-Functionalisation of Ketones Through Metal-Free Electrophilic Activation

Abstract

Triflic anhydride mediated activation of acetophenones leads to highly electrophilic intermediates that can undergo a variety of transformations when treated with nucleophiles. This electrophilic ketone activation gives access to α-arylated and α-oxyaminated acetophenones under metal-free conditions in moderate to excellent yields and enables extension to the synthesis of arylated morpholines via generation of vinylsulfonium salts. Computational investigations confirmed the transient existence of intermediates derived from vinyl triflates and the role of the oxygen atoms at the para position of aromatic ring in facilitating their stabilisation.

Keywords: sigmatropic rearrangement; vinyl cations; vinyl triflate; α-arylation; α-oxyamination.

Scheme 1

(a) Previous approaches to α‐arylation of ketones. (b) Hydrative α‐arylation of acetylenes. (c) Amide activation and ketone activation.

Scheme 2

a) Scope of α‐arylation of ketones and b) telescoped synthesis of α‐aryl‐α‐alkyl ketones; ^a 0.2 mmol scale; ^b 7.0 mmol scale; DTBMP −2,6‐di‐tert‐butyl‐4‐methyl‐pyridine.

Scheme 3

a) α‐Aminoxylation of acetophenones; b) Application of ketone activation to the synthesis of a morpholine.

Figure 1

Computed relative free energy profile (DLPNO‐CCSD(T)/def2‐TZVP//B3LYP‐D3/def2‐SVP, ΔG _298,DCM, kcal mol⁻¹) for the conversion of the intermediate A to the intermediate C (C′ in the case of the system III) via vinyl triflate B (taken as a reference 0.0 kcal mol⁻¹). The intermediate C (C′) leads to the final products. The pathway for the transformation of the intermediate C′ to the precursor of the sigmatropic rearrangement D is also depicted. See the SI for computational details.