Chiral phosphoric acid-catalyzed atroposelective iodination of N-arylindoles

Abstract

Axially chiral indoles have garnered significant attention due to their synthetic and biological importance. However, atroposelective halogenation of this scaffold has been rarely explored. This study presents a catalytic and enantioselective iodination of N-arylindoles, achieving precise control over the C-N stereogenic axis. The reaction is facilitated by a chiral phosphoric acid, which promotes iodination at the C-3 position of N-arylindole, followed by iodine migration and deprotonation. A hydrogen-bonding donor on the aromatic ring plays a key role in achieving high enantioselectivities. Under optimized reaction conditions, a wide range of substrates are well-tolerated, and subsequent reactions with various carbonyl electrophiles maintain enantioselectivity. Computational studies provide insights into the origin of enantioselectivity at the plausible enantiodetermining step.

Fig. 1. Organocatalytic enantioselective halogenation.

A Organocatalytic atroposelective halogenation via enantiodetermining halogenation. B Catalytic enantioselective halocyclization of indoles. C Catalytic and atroposelective C2-functionalization of indoles. D Proposed mechanism for chiral phosphoric acid-catalyzed atroposelective iodination of indoles.

Fig. 2. Substrate scope.

Unless otherwise noted, the reactions were conducted with 1 (0.050 mmol, 1.0 equiv), N-iodosuccinimide (0.075 mmol, 1.5 equiv), P2 (0.005 mmol, 10 mol%), PhMe (0.2 mL, 0.25 M). ^aThe reaction was performed at rt. ^bThe reaction was performed at −5 °C. ^cThe reaction was performed in CH₂Cl₂. ^dThe reaction was performed with 20 mol% of P2 at −5 °C.

Fig. 3. Substrate scope of substituted indoles.

Unless otherwise noted, the reactions were conducted with 1 (0.050 mmol, 1.0 equiv), N-iodosuccinimide (0.075 mmol, 1.5 equiv), P2 (0.005 mmol, 10 mol%), PhMe (0.2 mL, 0.25 M). ^aThe reaction was performed at −5 °C. ^bThe reaction was performed at rt.

Fig. 4. Mechanistic studies.

A Calculated rotational barriers of 1a, 2a, and 3a. B Catalytic reaction of 1a in CHCl₃. C Catalytic reaction of 1x. D Kinetic isotope experiment of 1a. E Plausible reaction mechanism. F Calculated transition state structures of 3a.

Fig. 5. Synthetic utility.

A 2-mmol scale reaction. B Further transformations.