Communication
condensation of 1 with aniline 2 followed by a bromine/iodine
exchange and Sonogashira coupling with phenyl acetylene 3.
In this way, compound 4a was obtained in a straightforward
manner. Functionalized derivatives of 4a are also accessible
through incorporation of the corresponding substituted deriva-
tives of 1, 2 and/or 3.[12]
Table 2. Optimization for reactions under iodine(III) catalysis.
With the required precursor 4a in hand, the intramolecular
indole synthesis was investigated for standard hypervalent io-
dine(III) reagents as promoters (Table 1). Initially, [bis(trifluoro-
Entry
Catalyst ([mol%])
Oxidant [equiv]
Yield [%][a]
1
2[b]
3
4
5
6
7
8
9
10
11
12[c]
13[c]
PhI (20)
PhI (20)
6 (20)
6 (10)
6 (5)
6 (5)
6 (10)
7 (5)
7 (10)
7 (10)
7 (20)
7 (20)
7 (20)
1.1
1.1
2.2
2.2
33
38
64
47
35
65
55
44
35
57
61
69
78
Table 1. Optimization for preformed iodine(III) reagents.
2.2
0.95
0.95
0.95
0.95
1.1
1.5
1.5
1.8
[a] Isolated yield after purification. [b] With one equivalent of acetic acid.
[c] In HFIP/(CH2Cl)2, 1/1 (v/v), and with sequential addition of the oxidant
in two portions (second one after 15 min reaction time) at 08C.
5a (X-ray)
acetic acid was chosen as benign terminal oxidant together
with the iodobenzene as potential catalyst. Some reactivity
was accomplished, but isolated yields of 5a remained low (en-
tries 1 and 2). Changing the catalyst to 2,2’-diiodobiphenyl 6
resulted in improved yields (64% at 20 mol% loading; entry 3).
Lowering the catalyst loadings led to diminished yields (en-
tries 4 and 5) together with the formation of unidentified deg-
radation products. To reduce the latter, the oxidant was em-
ployed as limiting agent, which increased the yield to 65% (at
5 mol% catalyst; entry 6). Surprisingly, at increased catalyst
loading of 10 mol%, product formation again became less se-
lective (entry 7). The same context was initially observed for
Kita’s catalyst 7[16] (entries 8 and 9). However, in this case an in-
crease in oxidant resulted also in improved yields (entries 10
and 11). Finally, the introduction of dichloroethane as solvent
component and two consecutive additions of the oxidant at
08C resulted in a protocol that provided 5a in 78% isolated
yield (entries 12 and 13).
Entry
Reagent
Solvent
T
[8C]
t
Yield
[%][a]
1
2
3
4
5
PIFA
PIFA
PIFA
PIDA
PIDA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
HFIP
25
0
10 min
6 h
10 h
12 h
45 min
57
78
64
<10[b]
85
À15
25
25
[a] Isolated yield after purification. [b] Based on crude reaction mixture
(1H NMR spectroscopy).
acetoxy)iodo]benzene (PIFA) was tested. Validating our as-
sumption, this reagent readily converted 4a into 5a in 57%
isolated yield (entry 1). The structure of 5a was unambiguously
assured by X-ray analysis at this stage.[13] Lowering the temper-
ature to 08C led to a significant increase in yield, whereas a fur-
ther decrease in temperature had no beneficial effect (entries 2
and 3). The related reaction with diacetoxy iodobenzene
(PIDA) led to almost no conversion (entry 4); however, upon
changing the solvent to hexafluoroisopropanol (HFIP),[14] com-
plete conversion within 45 min was observed (85% isolated
yield; entry 5).
Examples demonstrating the general scope of the present
reaction are presented in Scheme 2. For each compound, con-
ditions are given for one stoichiometric and one catalytic trans-
formation, demonstrating that the cyclization reactions to
compounds 5 can be conducted both with equimolar amounts
of a preformed iodine(III) reagent (protocols A,B) or under con-
ditions of a homogeneous aryliodine(I/III) catalysis (protocols
C,D).[12] A total of 18 successful examples with different substi-
tution pattern at all three arene rings exemplifies the capacity
of the present transformation to act as a general route towards
indole synthesis.
With established conditions for the formation of indole 5a
under stoichiometric conditions available, the possibility of a re-
action using catalytic amounts of the aryliodine was explored
(Table 2).[15] Initially, the PIDA/HFIP system was employed. Per-
A reasonable mechanistic context is depicted in Figure 2.
The reaction is initiated by interaction between the hyperva-
lent iodine reagent and substrate 4, most probably through
Chem. Eur. J. 2016, 22, 4351 – 4354
4352
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