A Triazole-Substituted Aryl Iodide with Omnipotent Reactivity in Enantioselective Oxidations

Abstract

A widely applicable triazole-substituted chiral aryl iodide is described as catalyst for enantioselective oxidation reactions. The introduction of a substituent in ortho-position to the iodide is key for its high reactivity and selectivity. Besides a robust and modular synthesis, the main advantage of this catalyst is the excellent performance in a plethora of mechanistically diverse enantioselective transformations, such as spirocyclizations, phenol dearomatizations, α-oxygenations, and oxidative rearrangements. DFT-calculations of in situ generated [hydroxy(tosyloxy)iodo]arene isomers give an initial rational for the observed reactivity.

Keywords: asymmetric oxidation; chiral hypervalent iodine compounds; organocatalysis; oxidation; stereoselective synthesis.

Figure 1

Best‐performing chiral aryl iodide catalysts for enantioselective oxygenations.

Figure 2

Structure of first‐ and second‐generation triazole catalysts.

Scheme 1

Catalyst synthesis. Reaction conditions: a) 7 (1 equiv), ethynylmagnesium bromide (1.25 equiv) at 0 °C for 2.5 h. b) 8 (1 equiv), CALB (6 mg/mmol of 8), isopropenyl acetate (1.5 equiv) in toluene at room temperature for 3 days c) ent 8 (1 equiv), benzyl azide (1.3 equiv), TTMCuCl (0.005 equiv) in water at room temperature for 17 h. d) 9 (1 equiv), 2,6‐lutidine (2 equiv), trialkylsilyl trifluoromethanesulfonate (1.2 equiv), in DCM at 0 °C for 6 h. The starting aldehydes are known in the literature and commercially available. For detailed synthetic procedures, see the Supporting Information.

Scheme 2

Enantioselective oxygenations and rearrangements catalyzed by 6 c in comparison with the best literature values. Detailed optimizations for each reaction are discussed in the Supporting Information. Due to missing comparable literature samples, the absolute configuration of the major isomers for 13, 15, and 19 has not been finally determined.

Scheme 3

a) Synthesis of N‐methyl triazole 6 d. b) Evaluation of the performance of 6 d in the Kita‐spirolactonization.

Figure 3

Calculated structures and relative free energies (G in kcal mol⁻¹) of hydroxy(tosyloxy) iodobenzene isomers of 5‐OH (a) and 6 c‐OH (b). For isomers 5/6 c‐OH‐N and 5/6 c‐OH‐O the tosylate counterion has been omitted in the illustration. All non‐heteroatom‐bound hydrogens have been omitted as well. Structure optimization and frequency analysis was performed on the PBEh‐3c/ma‐def2‐SVP(O,N)/def2‐TZVP(I) level of theory. Final single‐point energies were calculated on a PWPB95/ma‐def2‐TZVP(O,N)/def2‐TZVPP(I) level of theory using a continuum solvation model (CPCM) in CHCl₃.