Mechanism of Visible Light-Mediated Alkene Aminoarylation with Arylsulfonylacetamides

Abstract

Alkene aminoarylation with arylsulfonylacetamides via a visible-light mediated radical Smiles-Truce rearrangement represents a convenient approach to the privileged arylethylamine pharmacaphore traditionally generated by circuitous, multi-step sequences. Herein, we report detailed synthetic, spectroscopic, kinetic, and computational studies designed to interrogate the proposed mechanism, including the key aryl transfer event. The data are consistent with a rate-limiting 1,4-aryl migration occurring either via a stepwise process involving a radical Meisenheimer-like intermediate or in a concerted fashion dependent on both arene electronics and alkene sterics. Our efforts to probe the mechanism have significantly expanded the substrate scope of the transformation with respect to the migrating aryl group and provide further credence to the synthetic potential of radical aryl migrations.

Keywords: Photoredox; aminoarylation; aryl transfer; nucleophilic aromatic substitution; radical cation.

Figure 1.

Selected modern strategies for arylethylamine synthesis. Clockwise from the top: refs. , & , , , , , , and (top). Arylethylamine pharmaceuticals (middle). Key insights disclosed within this work (bottom).

Figure 2.

Key mechanistic questions addressed in this work.

Figure 3.

Calculated ionization potentials of aminoarylation starting materials and free energy changes at 298 K (in kcal/mol) for the various reaction paths to the putative benzylic radical intermediate. The calculations were carried out using B3LYP(D3)/CBSB7+ with bulk solvation by DMF estimated using a conductor-like polarized continuum model (CPCM).

Figure 4.

Acid-base equilibria of benzoate and sulfonylacetamide starting materials along with calculated molecular orbitals (MOs)of the H-bonded benzoate-sulfonylacetamide complex (4A). Calculated MOs do not support MS-CPET pathway (Figure 3D) as H+ transfer is not predicted upon single electron oxidation of the complex. Stern-Volmer (SV) luminescence quenching of relevant starting materials (4B). The SV data also supports alkene radical cation hypothesis (Figure 3A) rather than sulfonylacetamide SPLET or MS-CPET (Figure 3B and 3D). Calculated bond dissociation enthalpies of benzenesulfonylacetamide and benzoic acid (4C). Hydrogen atom transfer from the latter to the former is endergonic. The calculations were carried out using B3LYP(D3)/CBSB7+ with solvation by DMF estimated using a polarized continuum model.

Figure 5.

Alkene scope features aryl alkenes (5A). Tetrabutylammonium salt experiments support sulfonylacetamide conjugate base addition to an alkene radical cation rather than sulfonacetamidyl radical addition to an alkene (5B). ^aYield determined by ¹⁹F NMR analysis of the crude reaction mixture.

Figure 6.

N–H Bond acidity effect on aminoarylation yield. ¹H NMR shifts obtained in MeCN-d₃. (6A). Effect of of acidic conditions (a), buffered conditions (b), and super-stoichiometric base loading (c) on the aminoarylation reaction of benzenesulfonylacetamide 1a and trans-anethole 2a. Sub-stoichiometric loading of base (standard) gives optimum reactivity (6B).

Figure 7.

Calculated reaction coordinates for the 1,4-aryl shift in the key benzylic radical intermediate derived from the reaction of benzenesulfonylacetamide 1m with trans-anethole and subsequent desulfonylation. Corresponding barriers for substituted benzenesulfonylacetamides are also shown. Figure 7A depicts the π-stacked reaction pathway in which the migrating aryl group interacts with the para-methoxyphenyl group from the trans-anethole model alkene. Figure 7B depicts the π-slipped reaction pathway in which the migrating aryl group does not have a significant interaction. Stepwise or concerted 1,4 aryl migrations are possible from either the stacked or slipped pathways, depending on the electronics of the migrating arene and the sterics of the alkene. The slipped pathway results in systematically higher energies, along with more substrates favoring concerted aryl transfer. This is due to the slipped species experiencing a destabilizing pseudo 1,3-diaxial interaction (depending on the substitution of the alkene starting material). (7B top right). The absence of this diaxial interaction results in a stable, slipped Meisenheimer-like intermediate (7B bottom right). INT2 and INT3 energies are the same for either pathway. The calculations were carried out using B3LYP(D3)/CBSB7+ with solvation by DMF estimated using a conductor-like polarized continuum model (CPCM).

Figure 8.

Diastereoselectivity rationale based on computed conformational analysis of benzylic radical intermediate. Calculations were performed at B3LYP/CBSB7 level of theory in DMF with dispersion corrections (A). ¹H LED-NMR reaction monitoring with benzenesulfonylacetamide 1a conducted according to optimized reaction conditions in DMF-d₇. In situ alkene isomerization still maintains the observed >20:1 d.r. (B).

Figure 9.

Diverse aryl scope of alkene aminoarylation. Simply heating reactions with challenging electron-neutral or electron-rich substrates helped to recover desired reactivity in line with their higher calculated TS1/TS1’ energies (Figure 7). Reactions run at RT unless otherwise noted. All yields are isolated yields. The d.r. is > 20:1 unless otherwise noted.

Figure 10.

Correlation of the rate of aminoarylation with σ⁻ is consistent with increasing electron density on the benzenesulfonyl moiety in the rate-determining step of the reaction.

Figure 11.

No observed stereochemical scrambling is observed when the rac-5a kinetic probe is subjected to the optimized reaction conditions, suggesting that aryl migration is faster than ring opening of the cyclopropyl cyclohexadienyl radical (estimated to be 1.3 ×10⁸ s⁻¹).

Figure 12.

Refined mechanism of alkene aminoarylation informed by the studies detailed herein.