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Liu et al. Chem Synth 2023;3:11 https://dx.doi.org/10.20517/cs.2022.46 Page 3 of 8

Although the reaction is conceptually feasible, substantial challenges could lie in achieving the
enantioselective construction of this framework. In contrast with prior studies that employ iminoquinone
substrates to generate six-membered (hetero)biaryls, the lower rotational barrier of five-membered 3-
arylindole scaffolds might promote racemization and compromises the reaction enantioselectivity. The
configuration stability of such scaffolds is typically lower than the six-membered (hetero)biaryl
atropisomers [26,27] . To impede the free rotation around the newly formed C-C axis, we sought to amplify the
steric effect at the iminoquinone moiety or at the C2-position of indoles. On the other hand, the presence of
multiple reactive sites on both reacting substrates could interfere with the control of regio- and
enantioselectivity in the synthesis of 3-arylindole atropismers 3. In this regard, a suitable bifunctional
organocatalyst such as chiral phosphoric acid (CPA) should overcome the substrate-imposed selectivity
bias, thereby providing exquisite chemo- and stereoselectivity control during the C-C bond formation. In
addition, the N-protecting groups of iminoquinones could be a useful tuning parameter to modulate
selectivities.

EXPERIMENTAL
Chiral phosphoric acid (R)-C6 (5 mol%), 1 (0.28 mmol) and 2 (0.20 mmol) were added to a Schlenk tube,
then 4 mL of 1,2,4-trichlorobenzene was added via syringe in one portion. Upon the completion of the
reaction (about 1 h), the mixture was purified by preparative TLC (CH Cl /PE = 5/1 to 6/1) to give the pure
2
2
products 3.

RESULTS AND DISCUSSION
To validate the approach, we initiated exploration with N-benzoyl iminoquinone 1a and 2-(tert-butyl)-1H-
indole 2a as the model nucleophile in view of its good nucleophilicity. The large steric hindrance at C2-
position was expected to stabilize the newly formed chiral axis. Different chiral phosphoric acids were first
evaluated and all were found to smoothly promote the model reaction to afford axially chiral product 3a at
room temperature (see Supplementary Materials for details). This screening revealed (R)-C6 to afford the
best overall product yield and enantioselectivity. Other solvents were subsequently investigated based on (R)
-C6 as the optimal catalyst. The discovery that toluene could deliver better enantioselectivity than
dichloromethane and 1,2-dichloroethane led us to screen a series of benzene-derived solvents. 1,2,4-
trichlorobenzene was thus chosen as the reaction solvent due to its best performance. Having noticed that
further fine-tuning of other parameters did not improve the results (3a, 88% yield, 78% ee, Scheme 2), we
turned to modulating the N-protecting group of iminoquinones for a breakthrough. As shown in Scheme 2,
we were delighted to find that the replacement of H atom by Cl atom at C2-position on the benzoyl group
would enhance the product ee to 86% (3b). When the C2 and C6 positions were occupied by Cl and Br
substituents respectively, product 3c could be derived with 94% ee under the same conditions (see
Supplementary Materials for details). The dramatic decrease of yield and ee value (3d, 34%, 33% ee)
observed for 1d suggested the great influence that the iminoquinone substituents have had on the reaction.

The substrate generality of iminoquinones was then systematically examined under optimal reaction
conditions. As shown in Scheme 3, all of the tested iminoquinones reacted smoothly with 2a to afford the
corresponding products with moderate to high efficiencies (up to 94% yield and 94% ee). Notably, different
aromatic substituents and substitution positions on the benzoyl group were tolerated. Overall, various
halogen atoms (F, Cl, Br, I) or Me group could be incorporated as the C2 and C4 substituents without
significant influence on the reaction outcomes. The benzoyl group could also bear 2,4,6-trisubstitution with
Cl or Me groups to afford 3m and 3n in good results. Nonetheless, slightly inferior enantioselectivities
(84%-87% ee) could be seen for substrates with methyl substitutions (3g and3n) or with methoxy group (3j).