Journal of the American Chemical Society
Communication
a
Table 1. Reaction Development
reaction is not limited to aliphatic olefins, but also the phenyl-
substituted olefin 1h gave the corresponding product 2h in
8
8% yield and 95:5 er. Methyl substituents at any of the benzo-
positions (4, 5, 6, and 7) of the indole core did not hinder the
recognition with the catalyst, and products 2i−2l formed with
equally high enantioselectivities. The annulated substrates,
benzo[g]indole and tetrahydrocyclopenta[g]indole, also fur-
nished the desired products 2m and 2n in excellent yields and
enantioselectivities. Furthermore, halogen substituents as
potential synthetic handles for future modifications, as well
as electron-rich alkoxy substituents, were well tolerated (2o−
2
s). Notably, terminal dioxoborolane-, azido-, and iodo-
substitution at the alkyl chain of the olefin fragment gave
direct and highly enantioselective access to tetrahydrocarba-
zoles 2t−2v, illustrating the somewhat unexpected functional
group tolerance of our strong acid catalysts. The absolute
configuration of boronate product 2t was determined by
single-crystal X-ray diffraction, and the configuration of all
other products was assigned by analogy.
To further demonstrate the synthetic utility of the
hydroarylation products, boronate 2t was oxidatively hydro-
lyzed to the corresponding primary alcohol 2w with complete
3
2
retention of enantiopurity. Additionally, a C(sp )−C(sp )
Suzuki−Miyaura cross-coupling with 2-bromonaphthalene
provided compound 2x in 77% yield and, once again, without
any erosion of enantiopurity. The subjection of azido-
functionalized tetrahydrocarbazole 2u to a sequential N-
ethylation, azide reduction, and N,N-dimethylation provided
the first enantioselective synthesis of ammonium salt 8, in 41%
overall yield and with retention of enantiopurity, the racemic
entry catalyst T (°C) conv. (%) yield 2a (%) isom. (%)
er
1
2
3
4
5
6
7
8
9
1
3
4
5
6
7a
7b
7c
7d
7e
7e
80
80
80
80
80
80
80
80
80
60
41
47
13
55
34
30
<10
45
90
93
85
93
93
95
5
54:46
44:56
53:47
47:53
49:51
56:44
88:12
88:12
90:10
95:5
trace
trace
9
95
trace
full
full
full
full
full
23
mixture of which is being investigated as an antidepressant.
Keen on understanding the underlying mechanism of our
hydroarylation, we performed several control experiments
b
0
(
Scheme 1). Moderately acidic chiral Brønsted acid catalysts
a
Reactions were performed with substrate 1a (0.02 mmol), catalyst (2
such as CPAs have been shown to typically operate via a
mol %) in methylcyclohexane (CyMe, 0.2 mL); conversions (conv.),
yields of 2a, and olefin isomerizations (isom.) were determined by H
NMR analysis with mesitylene as an internal standard; enantiomeric
ratios (er’s) were measured by HPLC. When the reaction was not
18b,c
1
bifunctional, double-hydrogen bonding mechanism.
As a
consequence, the enantioselectivity and reactivity of CPA-
catalyzed reactions involving a nucleophilic indole can
massively erode upon N-substitution due to the lack of a
carried out in the dark, byproducts and lower yields were observed.
b
24
48 h.
recognition and activation element. In contrast, we found
that N-methylated indole 9 readily converted to the
corresponding product under our standard conditions, albeit
with a significantly reduced enantioselectivity of 71:29 er
(Scheme 1A). This observation is consistent with a bifunc-
tional enantiodiscrimination mechanism involving hydrogen
bonding interactions in a putative ion-pairing scenario.
(
entry 7, 88:12 er). Closer inspection of the crystal structure of
catalyst 7c (see Supporting Information) revealed extensive
π−π-interactions between the 3,3′-substituents and the
aromatic inner core, significantly influencing the shape of the
confined, chiral microenvironment. We reasoned that more
electron-rich catalyst substituents could potentially stabilize
both the π−π-interactions and the critical cationic inter-
mediate. Indeed, with methoxy-substituted catalyst 7d, yields
could be increased (entry 8, 93%). Finally, we identified IDPi
Electrophilic aromatic substitutions of indoles have been
shown to operate through a direct reaction at C-2 or the more
nucleophilic C-3 position, followed by a migratory opening of a
25,26
spiroindolenine intermediate.
We approached the impor-
7
e as the optimal catalyst, which, in addition to the 4′-methoxy
tant mechanistic question of how the cyclization occurs
experimentally in three different ways (Scheme 1B, C, and
D). First, removal of one methylene group from the alkyl
tether between indole and olefin in substrate 11 would lead to
the corresponding tetrahydrocyclopenta[b]indole 12, the
formation of which, if nucleophilic attack would proceed
directly from C-2, would be expected to be kinetically at least
as favorable as the corresponding six-membered ring
formation. However, even after stirring olefin 11 at 120 °C
for 2 d in the presence of 5 mol % of catalyst 7e, product 12
could not be observed, excluding direct reaction at C-2. This
result is consistent with the initial C-3 spirocyclization
mechanism, which in this specific case is not viable because
group, features two n-hexyl chains in the 3′- and 5′-positions of
the biphenyl system, affording the tetrahydrocarbazole 2a in
both excellent yield and enantioselectivity (entry 10, 95%, 95:5
er).
The outstanding performance of catalyst 7e was then further
challenged with several different substrates to explore the
scope of the hydroarylation. In general, the reaction tolerates
an array of substituents with differing steric and electronic
properties, in addition to sensitive functional groups. As
displayed in Table 2, irrespective of the alkyl groups attached
to the olefins, the corresponding tetrahydrocarbazoles 2a−2g
were formed in excellent yields and enantioselectivities. The
27
6
76
J. Am. Chem. Soc. 2021, 143, 675−680
Zhang, Pinglu
