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. 2020 May 4;59(19):7598-7604.
doi: 10.1002/anie.202001956. Epub 2020 Mar 11.

Iridium-Catalyzed Enantioselective Intermolecular Indole C2-Allylation

James A Rossi-Ashton  1 , Aimee K Clarke  1 , James R Donald  1 , Chao Zheng  2 , Richard J K Taylor  1 , William P Unsworth  1 , Shu-Li You  2
Affiliations

Iridium-Catalyzed Enantioselective Intermolecular Indole C2-Allylation

James A Rossi-Ashton et al. Angew Chem Int Ed Engl. .

Abstract

The enantioselective intermolecular C2-allylation of 3-substituted indoles is reported for the first time. This directing group-free approach relies on a chiral Ir-(P, olefin) complex and Mg(ClO4 )2 Lewis acid catalyst system to promote allylic substitution, providing the C2-allylated products in typically high yields (40-99 %) and enantioselectivities (83-99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2-allylation, rather than C3-allylation followed by in situ migration. Steric congestion at the indole-C3 position and improved π-π stacking interactions have been identified as major contributors to the C2-selectivity.

Keywords: DFT calculations; allylic substitution; enantioselective synthesis; indole; iridium.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Intermolecular indole C2‐allylation.
Scheme 2
Scheme 2
Allylic alcohol and indole substrate scope for C2‐allylation procedure.[a] [a] Yields of isolated products after column chromatography are reported. Enantiomeric excess (ee) values were determined by HPLC analysis with a chiral stationary phase. The concentration 0.5 m is with respect to the allylic alcohol. [b] Branched:linear product ratio determined by analysis of 1H NMR spectrum of the crude reaction mixture. [c] As a 13:1 mixture of rotamers.
Scheme 3
Scheme 3
Substrate scope for C3‐allylation.[a] [a] Yields of isolated products reported. Enantiomeric excess (ee) values were determined by HPLC analysis with a chiral stationary phase. [b] 0.25 equiv Zn(OTf)2 used instead of Mg(ClO4)2 and reaction performed at RT.
Scheme 4
Scheme 4
Mechanistic investigations[a,b] [a] Reaction conditions: 5 a or 9 (0.52 mmol), 1 a, 1 e or 1 r (0.40 mmol), [Ir(cod)Cl]2 (4 mol %), L1 (16 mol %), Mg(ClO4)2 (0.10 mmol) in CH2Cl2 (2.0 mL) at 40 °C, 20 h. [b] 1H NMR yields of products reported based on a trimethoxybenzene internal standard. Enantiomeric excess (ee) values were determined by HPLC analysis with a chiral stationary phase.
Figure 1
Figure 1
Optimized structures of TS‐2 and TS‐3 and their calculated relative Gibbs free energy (in kcal mol−1). (a) and (b) side views; (c) and (d) Newman projections along the forming C−C bond. The ligands associated to the Ir center are omitted for clarity.
Scheme 5
Scheme 5
Aliphatic allylic alcohol experiment[a] [a] Reaction conditions: 2 a (0.52 mmol), 1 a or 1 p (0.40 mmol), [Ir(cod)Cl]2 (4 mol %), L1 (16 mol %), Mg(ClO4)2 (0.10 mmol) in CH2Cl2 (2.0 mL) at 40 °C, 20 h. [b] 1H NMR yields reported based on trimethoxybenzene internal standard. Enantiomeric excess (ee) values were determined by HPLC analysis with chiral stationary phase.
Scheme 6
Scheme 6
Proposed mechanism.
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References

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