Angewandte
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Chemie
naphthalene 6-phenyl- and 7-phenyl-substituted substrates
with different halides at the phenyl ring of aniline were also
tolerated and gave products 2h–2m with excellent yields and
enantioselectivity. The same results were observed with
substrates bearing a methoxyl group at the naphthalene and
a methyl (2n), fluoro (2o), or chloro (2p) group at the phenyl
rings. Furthermore, substrates with a bromo group at the
naphthalene along with a methyl (2q) or fluoro (2r) at the
phenyl rings were also investigated, and excellent chemical
yields and enantioselectivity were observed. The absolute
configuration of 2r was determined by X-ray single-crystal
diffraction analysis and other products were assigned by
analogy. Moreover, substituting the phenyl group of 1-((2-
To further expand the synthetic utility of the reaction, we
attempted to demonstrate that the products of the reaction
(as exemplified by 2a) can be selectively manipulated
(Scheme 3c). As expected, the indole framework in axial
biaryl 2a was a promising unit for chemical transformation.
Upon treatment of 2a with NIS in dichloromethane at 08C for
8 hours, the product 3a was formed in 85% yield without loss
of enantiomeric purity. Applying the standard conditions of
iodination by simply introducing the corresponding halogen
sources, such as NBS and NCS, afforded 3-bromoindole 3b
and 3-chloroindole 3c in high yields without any change in the
enantiomeric ratio. Protecting the hydroxy group of enantio-
pure 2a with triflate allowed a series of substitution reaction
on the 3-position of indole moiety to produce the corre-
sponding NO (3d), OAc (3e), SCN (3 f), and CHO (3g)
derivatives with moderate yields and excellent enantiopurity.
Furthermore, the hydroxy group of 2a could be readily
transformed into the corresponding amine under standard
conditions with good yield and excellent ee value (3h).
Moreover, axial chiral 2a was transformed into chiral
phosphine 3i, which could potentially be used as the organo-
(
tert-butylamino) phenyl) ethynyl)naphthalen-2-ol with
another naphthyl caused slight decreases in the reaction
yield and stereoselectivity (2s). It is noteworthy that the
optimized reaction conditions could be extended to a sub-
strate with a tosyl group on the nitrogen atom of 1-((2-
aminophenyl)ethynyl)naphthalen-2-ol to give the corre-
sponding axially chiral naphthyl-C2-indole 2t. Further inves-
tigation revealed that different sizes or electronegativity of
the substituents on the phenyl group or naphthalene of the
substrates did not influence the yields or stereoselectivity of
this organocatalytic asymmetric annulation process, since
products 2u–2ac were afforded with high yields and excellent
enantioselectivity.
After exploring the substrate scope of our reaction
system, a thermal racemization experiment with the prepared
axially chiral naphthyl-C2-indole was carried out and the half-
life of enantiopure 2a was about 9902 hours at 1108C in
toluene, thus indicating a high tolerance of axially chiral
naphthyl-C2-indole 2a toward racemization. The thermal
stability of compound 2a suggests that it has potential as
a precursor for chiral ligands or organocatalysts in asymmet-
ric synthesis.
To demonstrate the synthetic practicability of the method,
a decagram-scale synthesis of axially chiral naphthyl-C2-
indole 2a was performed under the optimal reaction con-
ditions (Scheme 3). Starting from 1.0 g of 1a, the axial chiral
product 2a was obtained with excellent chemical yield and
enantioselectivity (Scheme 3a, 98% yield, > 99% ee). Next,
we fixed the amount of 1a at 50.0 g and lowered the catalyst
loading from 10 mol% to 5 mol%, and the desired asym-
metric annulation proceeded smoothly (Scheme 3b). After
completing the reaction and removing the solvent, enantio-
merically pure 2a was easily isolated through recrystallization
of the residues from DCM/hexane (1:10) in 90% yield and
[11]
catalyst in asymmetric transformations.
To further explore the utility of the obtained axially chiral
naphthyl-C2-indole skeleton, some asymmetric transforma-
tions were conducted by using product 3i as an organo-
catalyst. First, we investigated the performance of 3i as an
[
12]
organocatalyst in the aza-Baylis–Hillman reaction
of N-
sulfonated imines and acrolein. As shown in Scheme 3d, the
corresponding aza-Baylis–Hillman adduct was afforded in
good yield with high ee (95% yield, 88% ee) in the presence
of 3i. Second, we verified the efficiency of 3i as an organo-
catalyst for asymmetric formal [4+2] tandem cyclizations
between isatylidenemalononitriles and activated dienes
(Scheme 3e). Under mild reaction conditions, multistereo-
genic spirocyclic oxindole was obtained in high yield with
excellent enantioselectivity and diastereoselectivity (95%
[
13]
yield, 96% ee, > 20:1 dr).
In summary, we have established the first organocatalytic
enantioselective construction of chiral aryl-C2-indole skele-
tons through the asymmetric annulation of ortho-alkynylani-
lines. The strategy developed above was applicable to deca-
gram-scale preparations (50.0 g) and almost quantitative
yields were obtained with perfect enantioselectivity through
simple recrystallization without column chromatographic
separation. In addition, we were pleased to find that the
recovered catalyst A could be readily reused without
significant loss of catalytic activity and enantioselectivity.
The synthetic utility of this method was demonstrated
through useful functional-group transformations of the prod-
uct. Furthermore, the obtained axially chiral naphthyl-C2-
indole could be used as a key skeleton for an organocatalyst
for enantioselective aza-Baylis–Hillman reaction and formal
[4+2] tandem cyclization. Further demonstration of the utility
of the chiral aryl-C2-indole skeletons in asymmetric catalytic
transformations is currently underway in our laboratory.
>
99% ee. In addition, without any additional separation of
trace amounts of 2a or the catalyst, the obtained filtrate was
dried under reduced pressure. Then, the starting material 1a
(
50.0 g) and solvent were recharged and subjected to the
asymmetric annulation under standard reaction conditions
without the addition of more catalyst and 2a was furnished in
9
4% yield and > 99% ee. The recovered catalyst A was
readily reused without significant loss of catalytic activity and
enantioselectivity, thus indicating that this method could be
easily adapted to the large-scale synthesis of axially chiral
naphthyl-C2-indoles.
4
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Angew. Chem. Int. Ed. 2019, 58, 1 – 7
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