Photoredox Fischer Indole Synthesis

Article abstract of DOI:10.1055/s-0037-1611535

Visible light photoredox conditions were applied to the traditional Fischer indole synthesis. N, N -Diarylhydrazones were efficiently converted into the corresponding indoles even at 30 °C by treatment with bromotrichloromethane in the presence of Ru(bpy) ₃ Cl ₂ ·6H ₂ O as the photocatalyst. Electrochemical study revealed the viability of oxidative quenching cycle for the photocatalysis, which set the basis for proposing the redox-based reaction mechanism.

Full text of DOI:10.1055/s-0037-1611535

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
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Synthesis
A. Kaga et al.
Paper
Photoredox Fischer Indole Synthesis
Atsushi Kagaa
Tomohiro Fukushimab
Jun Shimokawa*c
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Masato Kitamura*a
a
Graduate School of Pharmaceutical Sciences, Nagoya University,
Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
kitamura@os.rcms.nagoya-u.ac.jp
b
c
Department of Chemistry, Faculty of Science, Hokkaido University,
North 10 West 8, Kita-ku, Sapporo, Hokkaido 060-0810, Japan
Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-
8502, Japan
shimokawa@kuchem.kyoto-u.ac.jp
Received: 25.02.2019
a. Typical Fischer Indole Synthesis
Accepted after revision: 16.04.2019
Published online: 09.05.2019
DOI: 10.1055/s-0037-1611535; Art ID: ss-2019-f0125-op
R1
R2
R1
R2
H
[3,3]-sigmatropic
rearrangement
H+
or D
N
N
Abstract Visible light photoredox conditions were applied to the tradi-
tional Fischer indole synthesis. N,N-Diarylhydrazones were efficiently
converted into the corresponding indoles even at 30 °C by treatment
N
R3
N
R3
1
2
R1
R2
R1
R1
with bromotrichloromethane in the presence of Ru(bpy) Cl ·6H O as
R2
R2
3
2
2
H+
the photocatalyst. Electrochemical study revealed the viability of oxida-
tive quenching cycle for the photocatalysis, which set the basis for pro-
posing the redox-based reaction mechanism.
N
N
R3
NH3
– NH3
– H+
N
N
R3
H
R3
3
4
5
Key words Fischer indole synthesis, [3,3]-sigmatropic rearrange-
ment, photoredox, radicals, hydrazones, cyclic voltammetry
b. Modified Methodology with Trifluoroacetylation as the Activation4
TFAA (2.0 equiv)
collidine (3.0 equiv)
Fischer indole synthesis is a well-known reaction that
N
THF, 0 °C
4%
N
CF3
N
N
has a long history and broad range of applications in organ-
6
7
9
Ph
Ph
O
1
ic synthesis. This traditional transformation is still often in
H
use because of its ready availability of the starting materials
and economical one-step experimental procedure. Various
acids and activating methods have already been developed
for this reaction (Scheme 1a). Typically, the reaction pro-
ceeds from hydrazone 1 via the formation of alkenylhydra-
zine 2 that then goes through [3,3]-sigmatropic rearrange-
ment, cyclization to form indoline 4, and elimination of am-
monia that lead to the core of indole 5. In addition to the
use of typical Brønsted acids as reagents/catalysts that are
occasionally associated with side reactions, thermal reac-
tion conditions are sometimes employed to give better re-
sults even though high temperature is required for efficient
CF3
O
N HN
Ph
–
CF3CONH2
53%
N
Ph
THF, 65 °C
8
9
c. Photoredox Fischer Indole Synthesis via Novel Activation of Hydrazone
(
This work)
t-Bu
t-Bu
hν
photoredox catalyst
N
N
N
&
N
10
oxidant
11
Ph
Ph
t-Bu
t-Bu
indoles
2
transformation (180–250 °C). These potential drawbacks
H
prompted chemists to develop alternative reaction condi-
3
tions for the Fischer indole synthesis. One of the most in-
N HN
N
teresting activating reagents that has been developed is tri-
12
Ph
13
Ph
4
fluoroacetic anhydride with which trifluoroacetylation of
Scheme 1 Fischer indole synthesis and its mode of activation on hy-
2
sp nitrogen atom of hydrazone 6, instead of protonation,
drazone moiety
mediates the activation of hydrazone moiety to form the
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

B
Synthesis
A. Kaga et al.
Paper
isolable trifluoroacetylated hydrazine 7 (Scheme 1b). Final
removal of trifluoroacetamide from indoline intermediate 8
gives indole target 9. During our research campaign toward
the standard substrate as the precursor to indole 13. Table 1
shows the details of our optimization of the conditions. The
scope of oxidants was examined first. Hydrazone 10 was re-
acted with arrays of oxidants (1.5 equiv) under the irradiat-
ing conditions (450 nm) in the presence of
Ru(bpy) Cl ·6H O (14, 1.0 mol%) in DMF. Bromotrichloro-
5
various application of photoredox reaction conditions, we
envisioned to implement this concept to Fischer indole syn-
thesis as an attempt to develop milder reaction conditions.
Herein, we describe novel photoredox conditions for Fisch-
er indole synthesis of certain diphenylhydrazones (Scheme
3
2
2
methane (BrCCl ) showed better reactivity than diethyl bro-
3
momalonate or carbon tetrachloride (Table 1, entries 1–3).
With bromotrichloromethane as the best performing oxi-
dant, the solvent effect was examined next. As can be seen
from entries 4–6, lower conversion of 10 was observed in
DMSO, THF, and CH Cl . By contrast, the treatment of 10 in
1c). This manuscript deals with the brief scope of the devel-
oped reaction, as well as the mechanistic reasoning of this
novel transformation as a foundation to further researches.
For the optimization of the reaction conditions, 4-tert-
butylcyclohexanone diphenylhydrazone 10 was selected as
2
2
methanol improved the reaction efficiency, providing in-
Table 1 Optimization of the Reaction Conditionsa
t-Bu
t-Bu
photocatalyst (1.0 mol%)
oxidant, hν (450 nm)
N
solvent
0 °C, time
N
N
3
10
13 Ph
Ph
2
+
2
+
+
PF6–
N
N
F3C
2PF6–
Cl–
F
F
2
t-Bu
t-Bu
N
N
N
N
Ru
N
N
Ir
N
N
N
N
N
N
N
N
N
N
F
Ru
N
F
N
N
N
F3C
Ru(bpz)3(PF6)2 (16)
Ru(bpy)3Cl2•6H2O (14)
[Ir{dF(CF3)ppy}2(dtbbpy)]PF6 (15)
Entry
Oxidant
Photocatalyst
Solvent
Conv. (%)b
Yield (%)b
1
2
3
4
5
6
7
8
9
BrCCl
BrCH(CO
CCl
3
14
DMF
DMF
DMF
DMSO
THF
>99
83
48
28
40
45
22
17
64
73
7
2
Et)
2
14
4
14
60
BrCCl
BrCCl
BrCCl
BrCCl
BrCCl
BrCCl
BrCCl
BrCCl
BrCCl
BrCCl
BrCCl
3
3
3
3
3
3
3
3
3
3
3
14
95
14
31
14
CH
2
Cl
2
39
14
MeOH
EtOH
90
14
>99
17
14
t-BuOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
1
1
1
1
0
14
>99
>99
14
85 (83)c
85
6
1
15
2
16
3
none
none
1
1
1
4d
>99
90
a
The reactions were carried out using hydrazone 10 (0.1 mmol) and oxidant (1.5 equiv) in the presence of photocatalyst (1.0 mol%) in solvent (0.05 M) at 30 °C
with irradiation of blue LED (450 nm) under an argon atmosphere for 2 h.
b 1
H NMR yields.
c
Isolated yield.
d
Reaction time was 8 h.
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Synthesis
A. Kaga et al.
Paper
dole 13 in 64% yield (entry 7). Screening of other alcoholic
solvents (entry 8–10) revealed that 2-propanol was the op-
timal solvent among examined (83% isolated yield, entry
a4d
TFAA
collidine
N
N
N
CF3
1
0). Change of the photocatalyst to [Ir{dF(CF )ppy} (dtbb-
N
3
2
N
N
THF
65 °C
THF
0 °C
1
7
48%
18
69%
83%
Ph
19
py)]PF6 (15) (entry 11), showed comparable reactivity,
while Ru(bpz) (PF ) (16) mediated more sluggish reaction
Ph
Ph
O
4
h
3
6
2
b
(entry 12). Interestingly, the conditions without any photo-
3 2 2
Ru(bpy) Cl ·6H O (1.0 mol%)
BrCCl3 (1.5 equiv), hν (450 nm)
catalyst gave the same result under the prolonged reaction
conditions (entries 13, 14). From the optimization above,
N
N
i-PrOH
30 °C, 4 h
1
7
Ph 19
Ph
(
1.0 mmol)
the conditions of entry 10 [hydrazone (0.05 M), BrCCl (1.5
3
equiv), 14 (1.0 mol%), irradiation (450 nm), 2-propanol]
was determined to be the best conditions.
Scheme 2 a) Miyata/Naito’s results with TFAA as the activation re-
agent. b) Our results on photoredox Fischer indole synthesis.
To briefly illustrate the scope of the reaction, several
substrates were subjected to the present reaction condi-
tions. Scheme 2 shows the results with 3-pentanone di-
phenylhydrazone 17. As previously reported, activation by
TFAA gives the trifluoroacetate 18. Subsequent heating in
THF at 65 °C mediates [3,3]-sigmatropic rearrangement and
formation of indoline moiety, followed by the ready elimi-
nation of trifluoroacetamide to give indole 19 (Scheme
a4d
TFAA
collidine
N
N
CF3
N
THF, 0 °C
N
20 Ph
56%
H
Ph
O
21
+
4d
a). Our optimized reaction conditions to 17 gave the
same indole 19 in good yield in one step even at 30 °C
Scheme 2b). Cyclopentanone diphenylhydrazone 20 is re-
ported to give trifluoroacetyl adduct 21 when treated with
N
NHTFA
N
2
22
Ph
23
Ph
THF, 65 °C, 5 h: 99%
+
+
0%
(
xylene, 140 °C, 4 h: 0%
92%
b
4d
TFAA and collidine (Scheme 3a). Interestingly, heating 21
in THF at 65 °C gives the cyclized indoline product 22. This
indicated the ready [3,3]-sigmatropic rearrangement and
the cyclization to form indoline moiety, while the elimina-
tion of trifluoroacetamide does not proceed readily. This
fact could be ascribed to the formation of strained iminium
cation intermediate and product that retarded the elimina-
tion. Under the refluxing conditions of xylene at 140 °C, this
elimination proceeds to afford the indole product 23 in
good yield. Our new photoredox conditions for the same
substrate 20 gave the indole product 23 in 70% yield even at
Ru(bpy)3Cl2·6H2O (1.0 mol%)
BrCCl3 (1.5 equiv), hν (450 nm)
N
N
N
i-PrOH
30 °C, 8 h
Ph
20
Ph
70% 23
(
1.0 mmol)
Scheme 3 a) Miyata/Naito’s results. b) Our results on photoredox
Fischer indole synthesis.
The mechanism of this photoredox Fischer indole syn-
thesis has two possibilities (Scheme 4). Cycle A involves the
oxidative quenching cycle where photoactivated ruthenium
30 °C, with the prolonged reaction time (Scheme 3b). The
species [Ru(bpy)3]2 is oxidized by the oxidant (BrCCl is re-
+*
formation of indole 23 was not associated with the forma-
tion of any remaining intermediate, indicating the in-
creased tendency toward the removal of the nitrogen func-
tionality from the indoline intermediate. Our preliminary
study indicated almost ignorable reactivity for the synthe-
sis of NH, N-Me, N-Bn, and N-Boc indoles.
3
duced first), and the other, cycle B, involves the reductive
quenching where the photoactivated species is reduced by
the hydrazone (hydrazone is oxidized first). Photophysical
and electrochemical experiments were thus conducted to
see the electrochemical reactivity of the reactants and to
hydrazone
hydrazone+
hydrazone
hydrazone+
Oxidative
Quenching Cycle
Reductive
Quenching Cycle
Ru(bpy)3]3+
[Ru(bpy)3]2+
[Ru(bpy)3]2+
*
[Ru(bpy)3]+
BrCCl3
[
A
B
–
Br
+
CCl3
hν
hν
–
BrCCl3
[Ru(bpy)3]2+
*
[Ru(bpy)3]2+
Br
+
CCl3
Scheme 4 Two possible catalytic cycles for the photoredox Fischer indole synthesis
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D
Synthesis
A. Kaga et al.
Paper
+
7
determine the reaction mechanism in the current photo-
redox Fischer indole synthesis.
First, luminescent quenching experiment was conduct-
ed to determine the plausible mechanistic cycles A and B.
As shown in the data in Supporting Information, similar lu-
that of Ru3+ (E1/2III/II = +1.28 V [vs Fc*/Fc* ]), which also sup-
ports the subsequent oxidation step (Table 1, entry 11). In
turn, the excited species [Ru(bpz) ] (E1/2
Fc*/Fc* ]) has weaker oxidation potential for the reduction
of BrCCl . This is consistent with the slower reaction (entry
2+*
III/*II
= –0.27 V [vs
3
+
12
3
minescent quenching of photoactivated Ru(bpy) Cl2 was
12).
3
observed with low solution concentration. This result indi-
cated the possibility of electron transfer between the pho-
tocatalyst and both of the substrates. However, it is still dif-
ficult to exclude the possibility of back-electron transfer. To
clarify the working mechanism of the reaction, electro-
chemical experiments were next examined. Figure 1 shows
the cyclic voltammogram of hydrazone 10 (blue) referenced
+
to redox couple of decamethylferrocene (Fc*/Fc* ) (black).
In this manuscript, reported electrochemical potentials of
known compounds versus SCE was converted to the values
+
referenced to Fc*/Fc* (in 2-propanol) according to the Lay’s
6
+
report. Thus the redox potential of Fc*/Fc* (55 mV in 2-
propanol vs Ag/AgCl) was estimated to be 10 mV (vs SCE)
through the known potential of Ag/AgCl (–45 mV vs SCE).
Cyclic voltammogram of hydrazone 10 in Figure 1 indicates
almost ignorable amount of current at the excited state re-
Figure 1 Cyclic voltammograms (100 mV/s scan rate) of blank (black)
and hydrazone 10 (5.0 mM, blue) recorded in 0.1 M tetrabutylammoni-
um hexafluorophosphate 2-propanol electrolyte. Electrochemical po-
2+*
*II/I
duction potential of [Ru(bpy) ]
(E1/2
= +0.76 V [vs
3
+
7
Fc*/Fc* ]) (orange). This indicates the inability of
2+*
+
[
Ru(bpy)3] to oxidize hydrazone 10 within the reductive
tential was referenced to Fc*/Fc* .
quenching cycle. Reductive quenching cycle (cycle B) is thus
proposed unlikely for the current photoredox Fischer indole
synthesis. This is because our Fischer indole synthesis re-
quires BrCCl as oxidant. Photo-excitation of Ru(bpy) initi-
3
3
ates the catalytic reaction cycle. If Ru(bpy) initiates the re-
3
ductive quenching cycle, some intermediates from hydra-
zone should be observed. However, we did not observe the
product effectively. These results suggest that oxidative
quenching cycle with oxidant is plausible in terms of the
mechanistic investigation. The reaction could be thus con-
sidered to involve the oxidative quenching cycle (cycle A)
that mediates the well-known reduction of BrCCl (E
=
3
1/2,red
+
8
−0.19 V [vs Fc*/Fc* ]) at the oxidation potential of the pho-
tocatalyst. This was further confirmed by the cyclic voltam-
mograms in the presence of BrCCl (blue line) in Figure 2,
that indicate the cathodic current at the excited state oxida-
3
Figure 2 Cyclic voltammograms (100 mV/s scan rate) of blank (black)
2
+
III/*II
and BrCCl (5.0 mM, blue) recorded in 0.1 M tetrabutylammonium
3
tion potential of [Ru(bpy) ] * (E
= –0.82 V [vs
3
1/2
hexafluorophosphate 2-propanol electrolyte. Electrochemical potential
+
7
Fc*/Fc* ]) at the green line. The reported reduction poten-
tials (E1/2,red) of CCl4 and BrCH(CO Et) are –1.94 V [vs
Fc*/Fc* ] and –0.63 V [vs Fc*/Fc* ], respectively. These val-
+
was referenced to Fc*/Fc* .
2
2
+
+
9
ues support that the single-electron reduction of BrCCl3
Collectively, the reaction mechanism is in accordance
+
2+
(
[
E1/2,red = –0.19 V [vs Fc*/Fc* ]) by the excited state
with the following proposal (Scheme 5). First, [Ru(bpy) ]
3
2+*
III/*II
+
2+*
Ru(bpy)3] (E1/2
= –0.82 V [vs Fc*/Fc* ]) is kinetically
(14) is photoactivated to [Ru(bpy) ] that reduces BrCCl to
3
3
3+
preferred than those of CCl and BrCH(CO Et) . These dis-
generate [Ru(bpy) ] , bromide anion, and trichloromethyl
4
2
2
3
cussions are consistent with the results of entries 10–12 in
radical. The radical species attacks the nitrogen atom of
C=N bond of hydrazone 10 leading to -aminoalkyl radical
24, which would be oxidized to cation 25 by single-electron
IV/*III
Table 1. With [Ir{dF(CF )ppy} (dtbbpy)]PF (E
= –0.90
3
2
6
1/2
+
10
V [vs Fc*/Fc* ]) as the photocatalyst, almost the same re-
dox characteristics indicate the same oxidative quenching
3+ 13
oxidation mediated by [Ru(bpy) ] . This regioselectivity
3
11
4+
mechanism. The ground state reduction potential of Ir
may be associated with the fact that electron-deficient rad-
icals such as acyl radicals are known to favor the attack at
intermediate (E1/2IV/III = +1.68 V [vs Fc*/Fc* ]) is similar to
+
10
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A. Kaga et al.
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t-Bu
BrCCl3
hν
BrCCl3
Br
+
CCl3
Br
N
– HBr
N
CCl3
Ph 30
Uncatalyzed Path
t-Bu
t-Bu
t-Bu
t-Bu
–
H+
N
N
N
N
N
N
CCl3
N
CCl3
N
CCl3
10
Ph
24 Ph
Ph 25
26
Ph
Oxidative
Quenching Cycle
t-Bu
[
Ru(bpy)3]3+
A
[Ru(bpy)3]2+
–
Br
+
CCl3
Ru(bpy)3]2+
hν
N
[
*
N
CCl3
BrCCl3
27
Ph
t-Bu
t-Bu
t-Bu
NH
Cl
H
H
Cl
Cl
Cl
–
H+
– Cl–
N
Ph
N
Ph
N
H
N HN CCl3
Ph
13
29
28
Scheme 5 Proposed reaction mechanism for the photoredox Fischer indole synthesis
nitrogen atom of imines.14 Deprotonation affords alkenyl-
hydrazine 26 that is then susceptible to [3,3]-sigmatropic
rearrangement to form a C–C bond to give 27. The following
cyclization forms indoline 28. The ease of elimination of ni-
trogen functionality under the current reaction conditions
indicate the increased leaving ability, possibly exerted by
the formation of iminium ion 29, formed by expelling the
chloride. Final removal of iminophosgene and isomeriza-
tion gives indole 13. Slow formation of indole 13 without
the addition of photocatalyst could be similarly reasoned by
plausible catalytic mechanism. Trichloromethyl radical is
suggested to attack the nitrogen atom of hydrazone moiety
and helps the formation of alkenylhydrazine as the efficient
substrate of [3,3]-sigmatropic rearrangement, followed by
the ready removal of nitrogen functionality for the facile
formation of indole core even at 30 °C.
All nonaqueous reactions were carried out under an inert atmosphere
of N in oven-dried glassware, unless otherwise noted. DMF, DMSO,
2
MeCN, and 2-propanol were distilled over CaH . All other reagents
considering the uncatalyzed photoactivation of BrCCl3 to
2
give bromine radical and trichloromethyl radical,15 which
were commercially available and used without further purification,
unless otherwise noted. Analytical TLC was performed on Merck pre-
coated analytical plates, 0.25 mm thick, silica gel 60 F254. Preparative
flash chromatography was performed using Silica Gel (AP-300, irregu-
would mediate a radical chain reaction to generate the ac-
tive species 24. This mechanism could account for the typi-
cal induction period of the reaction before following the
similar transformations to give the same alkenylhydrazine
1H and 13C NMR
lar, 38–75 m) purchased from Toyotakako Co., Ltd.
spectra were recorded on a JEOL JNM-ECA600 or JNM-ECZ600 spec-
1
trometer. All H NMR spectra are reported in units, parts per million
26 possibly through 30.
(ppm) downfield from TMS as the internal standard (0.00 ppm) or
In conclusion, novel photoredox Fischer indole synthesis
was developed employing the combination of photocatalyst
CHCl (7.26 ppm) and coupling constants are indicated in hertz (Hz).
3
Standard abbreviations are used for spin multiplicity. All 13C NMR
and BrCCl . From the results on the selected substrates, the
3
spectra are reported in ppm relative to the central line of the triplet
methodology thus developed suggests its usability for con-
structing N-aryl 2,3-disubstituted indoles. Mechanistic
studies revealed that the oxidative quenching cycle is the
for CDCl (77.0 ppm). High resolution mass spectra (HRMS) were ob-
3
tained on a Bruker micrOTOF II spectrometer. Melting points, deter-
mined on a Stanford Research Systems MPA100 melting point appara-
tus, are uncorrected.
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A. Kaga et al.
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2
-[4-(tert-Butyl)cyclohexylidene]-1,1-diphenylhydrazine (10);
(2.0 mL), which was degassed three times by freeze–thaw process.
BrCCl3 (15 L, 0.15 mmol) was added via syringe and the resulting
mixture was irradiated by blue LED. After stirring at 30 °C for 2 h, the
Typical Procedure for the Synthesis of N,N-Diphenylhydrazones
A 300 mL round-bottomed flask equipped with a magnetic stir bar
was charged under argon gas with 1,1-diphenylhydrazine (6.8 g, 37
mmol), 4-tert-butylcyclohexanone (5.4 g, 35 mmol), AcOH (20 L,
reaction mixture was quenched with sat. aq NaHCO (1 mL). The mix-
3
ture was partitioned between Et O and H O. The organic phase was
2
2
collected and the aqueous phase was extracted with Et O (2 ×). The
0
6
.35 mmol), and EtOH (70 mL). The resulting mixture was stirred at
0 °C for 15 h and cooled to r.t. The mixture was partitioned between
2
combined organic extracts were washed with brine and dried over
anhyd Na SO (ca. 1.0 g), filtered, and concentrated in vacuo. The resi-
Et O and H O. The organic phase was collected and the aqueous phase
was extracted with Et O (2 ×). The combined organic extracts were
washed with brine and dried (anhyd Na SO ), filtered; and concen-
trated in vacuo. The residue was purified by column chromatography
2
4
2
2
due was purified by column chromatography on silica gel (n-hex-
ane/EtOAc 1:0 to 200:1) to afford indole 13 (25.1 mg, 0.083 mmol,
2
2
4
8
3%) as a clear oil; R = 0.72 (n-hexane/EtOAc 5:1, UV, PMA).
f
1
on silica gel (n-hexane/EtOAc 100:1 to 40:1) to afford hydrazone 10
H NMR (CDCl , 600 MHz):  = 7.54–7.48 (m, 3 H), 7.40–7.35 (m, 3 H),
3
(
[
1
7.8 g, 24 mmol, 70%) as a pale brown solid, mp 58.0–59.0 °C; R = 0.59
n-hexane/EtOAc 5:1, UV, PMA (phosphomolybdic acid)].
7.23 (dd, J = 6.2, 2.1 Hz, 2 H), 7.11 (ddd, J = 13.8, 6.9, 2.1 Hz, 2 H), 2.92
(dd, J = 15.2, 4.8 Hz, 1 H), 2.69 (m, 1 H), 2.61 (dd, J = 16.5, 5.5 Hz, 1 H),
2.50 (m, 1 H), 2.09 (m, 1 H), 1.60 (ddd, J = 12.4, 4.8, 2.1 Hz, 1 H), 1.47
f
H NMR (CDCl , 600 MHz):  = 7.27 (t, J = 7.6 Hz, 4 H), 7.04 (d, J = 8.3
3
(ddd, J = 24.8, 11.7, 4.8 Hz, 1 H), 1.01 (s, 9 H).
Hz, 4 H), 7.00 (dd, J = 8.3, 7.6 Hz, 2 H), 3.10 (m, 1 H), 2.79 (m, 1 H),
.25 (ddd, J = 14.5, 13.1, 4.8 Hz, 1 H), 2.03 (m, 1 H), 1.76 (m, 1 H), 1.53
ddd, J = 14.5, 13.8, 5.5 Hz, 1 H), 1.33 (ddd, J = 13.1, 12.4, 4.1 Hz, 1 H),
13
2
(
1
C NMR (CDCl , 150 MHz):  = 138.1, 137.4, 135.9, 129.3, 127.8,
3
127.0, 126.9, 121.2, 119.6, 117.6, 111.4, 109.8, 45.3, 32.6, 27.5, 24.9,
24.1, 22.4.
.23 (m, 1 H), 0.99 (ddd, J = 13.8, 13.1, 4.1 Hz, 1 H), 0.85 (s, 9 H).
13
+
C NMR (CDCl , 150 MHz):  = 175.4, 148.6, 128.9, 122.5, 120.9, 47.2,
HRMS (APCI-MS, positive): m/z [M + H] calcd for C22H26N: 304.2060;
3
35.1, 32.4, 30.1, 27.8, 27.5, 26.5.
found: 304.2070.
+
HRMS (APCI-MS, positive): m/z [M + H] calcd for C22H29N : 321.2325;
2
found: 321.2335.
2-Ethyl-3-methyl-1-phenyl-1H-indole (19)
Reaction of hydrazone 17 (252 mg, 1.0 mmol), Ru(bpy) Cl ·6H O (7.5
3
2
2
2
-(Pentan-3-ylidene)-1,1-diphenylhydrazine (17)
Reaction of 3-pentanone (1.4 g, 16 mmol), 1,1-diphenylhydrazine
2.2 g, 12 mmol), AcOH (50 L, 0.88 mmol), and EtOH (10 mL) at 90 °C
mg, 0.010 mmol), BrCCl (150 L, 1.5 mmol), and 2-propanol (20 mL)
at 30 °C with irradiation of blue LED for 4 h gave indole 19 (196 mg,
3
0.833 mmol, 83%) as a clear oil after purification by column chroma-
(
tography on silica gel (n-hexane/EtOAc 1:0 to 100:1); R = 0.68 (n-
for 12 h gave hydrazone 17 (2.0 g, 7.9 mmol, 66%) as a pale yellow oil
after purification by column chromatography on silica gel (n-hex-
ane/EtOAc 20:1 to 10:1); R = 0.58 (n-hexane/EtOAc 5:1, UV, PMA).
f
hexane/EtOAc 5:1, UV, PMA).
1H and 13C NMR spectra were identical with the literature data.16
f
1
1
H NMR (CDCl , 600 MHz):  = 7.30 (dd, J = 8.6, 7.4 Hz, 4 H), 7.08 (dd,
H NMR (CDCl , 600 MHz):  = 7.55 (d, J = 7.6 Hz, 1 H), 7.52 (t, J = 7.6
3
3
J = 8.6, 1.0 Hz, 4 H), 7.04 (t, J = 7.4 Hz, 2 H), 2.49 (dd, J = 15.1, 7.6 Hz, 2
H), 2.31 (dd, J = 15.3, 7.7 Hz, 2 H), 1.26 (t, J = 7.6 Hz, 3 H), 0.90 (t, J = 7.7
Hz, 3 H).
Hz, 2 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.34 (d, J = 6.9 Hz, 2 H), 7.12 (ddd, J =
7.6, 6.9, 1.4 Hz, 1 H), 7.08 (ddd, J = 7.6, 6.9, 1.4 Hz, 1 H), 7.03 (d, J = 8.3
Hz, 1 H), 2.69 (dd, J = 15.2, 7.6 Hz, 2 H), 2.34 (s, 3 H), 0.99 (t, J = 7.6 Hz,
3 H).
13
C NMR (CDCl , 150 MHz):  = 179.0, 148.6, 128.9, 122.5, 120.8, 29.0,
3
13
25.0, 11.2, 9.8.
C NMR (CDCl , 150 MHz):  = 138.9, 138.4, 137.5, 129.3, 128.7,
3
+
128.3, 127.6, 121.1, 119.4, 117.9, 109.8, 107.2, 18.0, 14.3, 8.7.
HRMS (APCI-MS, positive): m/z [M + H] calcd for C17H21N : 253.1699;
2
found: 253.1707.
4-Phenyl-1,2,3,4-tetrahydrocyclopenta[b]indole (23)
2
-Cyclopentylidene-1,1-diphenylhydrazine (20)
Reaction of cyclopentanone (1.26 g, 15 mmol), 1,1-diphenylhydrazine
2.2 g, 12 mmol), AcOH (50 L, 0.88 mmol), and EtOH (10 mL) at 90 °C
Reaction of hydrazone 20 (250 mg, 1.0 mmol), Ru(bpy) Cl ·6H O (7.5
3
2
2
mg, 0.010 mmol), BrCCl (150 L, 1.5 mmol), and 2-propanol (20 mL)
3
at 30 °C with irradiation of blue LED for 8 h gave indole 23 (164 mg,
(
0.704 mmol, 70%) as a clear oil after purification by column chroma-
for 5 h gave hydrazone 20 (1.99 g, 7.95 mmol, 66%) as a pale yellow
solid after purification by column chromatography on silica gel (n-
hexane/EtOAc 20:1 to 10:1); mp 48.1–49.4 °C; Rf = 0.45 (n-hex-
ane/EtOAc 5:1, UV, PMA).
tography on silica gel (n-hexane/EtOAc 1:0 to 100:1); R = 0.64 (n-
f
hexane/EtOAc 5:1, UV, PMA).
1H and 13C NMR spectra were identical with the literature data.17
1
1
H NMR (CDCl , 600 MHz):  = 7.29 (ddd, J = 8.58, 7.38, 2.06 Hz, 4 H),
H NMR (CDCl , 600 MHz):  = 7.49 (m, 3 H), 7.44 (m, 3 H), 7.33 (m, 1
3
3
7
7
.07 (dd, J = 8.58, 1.20 Hz, 4 H), 7.04 (t, J = 7.38 Hz, 2 H), 2.58 (t, J =
.38 Hz, 2 H), 2.03 (t, J = 7.35 Hz, 2 H), 1.78–1.67 (m, 4 H).
H), 7.11 (m, 2 H), 2.90 (dd, J = 14.5, 7.6 Hz, 4 H), 2.55 (quint, J = 6.9 Hz,
2 H).
13
13
C NMR (CDCl , 150 MHz):  = 178.8, 148.2, 129.0, 122.8, 121.4, 33.8,
C NMR (CDCl , 150 MHz):  = 145.6, 140.9, 138.9, 129.4, 126.1,
3
3
31.6, 24.9, 24.4.
125.0, 124.7, 120.9, 120.3, 120.1, 118.6, 110.7, 28.3, 26.2, 24.6.
+
HRMS (APCI-MS, positive): m/z [M + H] calcd for C17H19N : 251.1543;
2
found: 251.1541.
Funding Information
3
-(tert-Butyl)-9-phenyl-2,3,4,9-tetrahydro-1H-carbazole (13);
This work was supported by the Kato Memorial Bioscience Founda-
tion, a Mitsubishi Tanabe Pharma Award in Synthetic Organic Chem-
istry, Japan, JSPS KAKENHI Grant Numbers 23590003, 25221301,
Typical Procedure for the Photoredox Fischer Indole Synthesis
A 20 mL oven-dried J. Young Schlenk tube equipped with a magnetic
stir bar was charged under argon with hydrazone 10 (32.0 mg, 0.10
mmol), Ru(bpy) Cl ·6H O (0.75 mg, 0.0010 mmol), and 2-propanol
15H05641, the Platform for Drug Discovery, Informatics, and Struc-
3
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

G
Synthesis
A. Kaga et al.
Paper
tural Life Science from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan, and the Advanced Catalytic
Transformation Program for Carbon Utilization (ACT-C) from the Ja-
Kimura, Y.; Takemoto, Y.; Tohnai, N.; Miyata, M.; Naito, T. Tetra-
hedron 2006, 62, 3629. (e) Miyata, O.; Takeda, N.; Naito, T.
J. Synth. Org. Chem. Jpn. 2006, 64, 1282.
pan Science and Technology Agency (JST).
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(5) (a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011,
40, 102. (b) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem.
Rev. 2013, 113, 5322. (c) Shaw, M. H.; Twilton, J.; MacMillan, D.
W. C. J. Org. Chem. 2016, 81, 6898. (d) Kärkäs, M. D.; Porco, J. A.
Jr.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683. (e) Romero,
N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611535.
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6) (a) Noviandri, I.; Brown, K. N.; Fleming, D. S.; Gulyas, P. T.; Lay,
P. A.; Masters, A. F.; Phillips, L. J. Phys. Chem. B 1999, 103, 6713.
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b) Bard, A. J.; Faulkner, L. R. Electrochemical Methods: Funda-
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G