Organic Letters
Letter
a
the transition-metal-free approach to generate an aryl radical
species, in combination with the established condensation of
aniline and ketone species, should serve as an ideal protocol to
access diversely substituted indole derivatives in a program-
mable manner under mild conditions.
Scheme 2. Synthesis of 2-Substituted Indoles
To evaluate the hypothesis, we attempted the coupling of 2-
iodoaniline (1) and acetophenone (a) in the presence of 3
equiv of KOt-Bu (Table 1). While the unassisted use of KOt-
a
Table 1. Optimization of Reaction Parameters
b
entry
promoter
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
80
80
80
80
80
80
80
80
60
60
18
18
18
18
18
18
18
18
18
8
10
63
48
39
39
19
83
86
P1 (0.4 equiv)
P2 (0.4 equiv)
P3 (0.4 equiv)
P4 (0.4 equiv)
P5 (0.4 equiv)
P6 (0.4 equiv)
P6 (0.2 equiv)
P6 (0.2 equiv)
P6 (0.2 equiv)
a
Reaction conditions: iodoaniline (0.50 mmol), ketone (1.0 mmol),
KOt-Bu (1.5 mmol), P6 (0.10 mmol), DMSO (1.5 mL), 60 °C, 8 h.
b
Yields of the isolated products. 3,4-Dimethoxyacetophenone was
used instead of acetophenone because it is more easily isolated.
9
10
80
82 (83)
(11a). In addition, substrates possessing two C−Cl or C−Br
bonds were successfully employed to provide the correspond-
ing indole products with multiple handles for further
elaboration (14a−17b). Remarkably, alkyl and benzyl
substituents at the nitrogen atom of the aniline derivatives
were well tolerated under the reaction conditions (18a−21a).
Subsequently, the scope of the ketone counterpart was
assessed by using various methyl ketones to afford 2-
substituted indole derivatives (Scheme 3). Both electron-rich
and electron-deficient acetophenones were successfully utilized
as reaction partners (1b−1g). In addition, halogen-containing
phenyl groups (1h−1k) as well as polycyclic aromatic
hydrocarbons, such as naphthalene (1l) and phenanthrene
(1m), were conserved. Of note, pharmaceutically important
heterocyclic moieties were conveniently introduced at the 2-
position of the indole system (1n−1s).14 Methyl ketones
bearing an alkyl substituent such as cyclopropyl (1t) and tert-
butyl groups (1u) were also viable substrates for the
transformation.
We next attempted to extend this methodology to the
preparation of 2,3-disubstitued indoles (Scheme 4). Propio-
phenone and butyrophenone furnished the corresponding
indole products with a C3 alkyl group in high yields (1a′ and
1b′). Tricyclic and tetracyclic indoles were readily prepared
from cyclic ketones (1c′−1e′), and a heteroatom substituent
was installed at the 3-position of indole (1f′). The use of an
aldehyde as a reaction partner, however, led to a significantly
diminished yield of the desired 3-phenyl indole (1g′).
Interestingly, in the case of phenylacetone and benzylacetone,
which have two possible positions for enolization, the product
originating from thermodynamically more stable enolate was
obtained (1h′ and 1i′). The regioselectivity trend of 1i′ is
consistent with that of the pioneering works of Bunnett and
Semmelhack, which cover the regioselectivity for the addition
of an aryl radical to an enolate when the formation of multiple
regioisomers is possible.15 Product formation at the methylene
side of the enolate is preferred over reaction at the methyl side.
mined by GC using dodecane as an internal standard. Yields in
parentheses are isolated yields.
Bu was virtually ineffective, the efficiency of the reaction was
significantly improved by adding a substoichiometric amount
of an organic promoter (entries 1−7). Among the various
promoters that were evaluated, 4,7-diphenylphenanthroline
(P6, bathophenanthroline) was the most potent in terms of
product formation, yielding more than 80% of indole product
(1a). Further optimization of the reaction revealed that the
reaction proceeded to completion in 8 h in the presence of 0.2
equiv of P6 at 60 °C, without notable loss of efficiency (entries
8−10). Of note, the coupling reaction could also be performed
near room temperature, although a longer reaction time was
required (entry 11).
With the optimized conditions in hand, we next evaluated
the generality of the reaction with substituted (Scheme 1, R1
and R4−R7) 2-iodoanilines (Scheme 2). A wide range of
electron-donating and electron-withdrawing substituents, in-
cluding alkyl, methoxy, cyano, nitro, and carboalkoxy groups,
were successfully installed into the products (2a−7a). Also, an
extended π-system was implemented on the indole structure
(8a). Moreover, halogen substituents, which can be utilized as
functional handles for late stage cross-coupling reactions, were
introduced at all the four positions of the 6-membered ring of
the core structure (9a−13b). Importantly, the selective
installation of a substituent at the 4-position of indole, which
is difficult to realize from simple precursors using other
methods,13 were achieved with a synthetically useful yield
1097
Org. Lett. 2021, 23, 1096−1102