Direct Synthesis of Indoles from Azoarenes and Ketones with Bis(neopentylglycolato)diboron Using 4,4′-Bipyridyl as an Organocatalyst

Article abstract of DOI:10.1021/acs.joc.0c02661

Multifunctionalized indole derivatives were prepared by reducing azoarenes in the presence of ketones and bis(neopentylglycolato)diboron (B2nep2) with a catalytic amount of 4,4′-bipyridyl under neutral reaction conditions, where 4,4′-bipyridyl acted as an organocatalyst to activate the B-B bond of B2nep2 and form N,N′-diboryl-1,2-diarylhydrazines as key intermediates. Further reaction of N,N′-diboryl-1,2-diarylhydrazines with ketones afforded N-vinyl-1,2-diarylhydrazines, which rearranged to the corresponding indoles via the Fischer indole mechanism. This organocatalytic system was applied to diverse alkyl cyclic ketones, dialkyl, and alkyl/aryl ketones, including heteroatoms. Methyl alkyl ketones gave the corresponding 2-methyl-3-substituted indoles in a regioselective manner. This protocol allowed us to expand the preparation of indoles having high compatibility with not only electron-donating and electron-withdrawing groups but also N- and O-protecting functional groups.

Full text of DOI:10.1021/acs.joc.0c02661

pubs.acs.org/joc
Article
Direct Synthesis of Indoles from Azoarenes and Ketones with
Bis(neopentylglycolato)diboron Using 4,4′-Bipyridyl as an
Organocatalyst
Luis C. Misal Castro, Ibrahim Sultan, Kohei Nishi, Hayato Tsurugi,* and Kazushi Mashima*
Cite This: J. Org. Chem. 2021, 86, 3287−3299
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Multifunctionalized indole derivatives were prepared by reducing azoarenes in the presence of ketones and
bis(neopentylglycolato)diboron (B2nep2) with a catalytic amount of 4,4′-bipyridyl under neutral reaction conditions, where 4,4′-
bipyridyl acted as an organocatalyst to activate the B−B bond of B2nep2 and form N,N′-diboryl-1,2-diarylhydrazines as key
intermediates. Further reaction of N,N′-diboryl-1,2-diarylhydrazines with ketones afforded N-vinyl-1,2-diarylhydrazines, which
rearranged to the corresponding indoles via the Fischer indole mechanism. This organocatalytic system was applied to diverse alkyl
cyclic ketones, dialkyl, and alkyl/aryl ketones, including heteroatoms. Methyl alkyl ketones gave the corresponding 2-methyl-3-
substituted indoles in a regioselective manner. This protocol allowed us to expand the preparation of indoles having high
compatibility with not only electron-donating and electron-withdrawing groups but also N- and O-protecting functional groups.
To overcome the above-mentioned drawbacks, various
synthetic strategies via the Fischer indole mechanism have
been developed over the last two decades, as shown in Scheme
1. Upon using activated alkynes such as diethyl acetylenedi-
carboxylate with N-methyl-N-phenylhydrazine, hydroamina-
tion and subsequent cyclization give N-methylindole via
enamine mediated by ZnCl2, reported by Beller et al. (Scheme
1A).6 Liang et al. prepared substituted indoles in a
regioselective manner using N-protected-N′-acetyl phenyl-
hydrazines as starting materials for copper-catalyzed N-
vinylation with vinyl bromides followed by treatment with
ZnCl2 (Scheme 1B).7 Aryldiazonium salts were applied to
indole synthesis: Antonchick et al. reported the multi-
component cascade synthesis of indole derivatives by mixing
INTRODUCTION
■
Indole is a synthetically valuable skeleton often involved in
versatile organic compounds such as pharmaceuticals, agro-
chemicals, dyes, and so on.1,2 Different kinds of straightforward
protocols for synthesizing indoles with various substituents
have been widely investigated over the last century.3,4 Among
them, Fischer indole synthesis by condensing phenylhydrazines
with ketones is the most versatile and broadly useful
methodology;5 nonetheless, the narrow substrate scope of
this reaction is attributed to the rather poor accessibility of
substituted phenylhydrazine derivatives, fairly low functional
group tolerance toward the required strong acidic conditions,
and low regioselectivity when using unsymmetrical ketones (eq
1).5b
Received: November 7, 2020
Published: February 8, 2021
https://dx.doi.org/10.1021/acs.joc.0c02661
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 3287−3299
3287

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 1. Modified Fischer Indolization (A−E) and This Work (F)
aryldiazonium salts, alkenes, and sodium triflinate as a CF3
source with AgNO3 (0.5 equiv) and H2O2 (excess) via the
generation of trifluoromethyl radicals under the reaction
conditions (Scheme 1C),8 while Knochel et al. developed a
highly regioselective and functional group-tolerant method
with in situ-generated alkylzinc reagents under microwave
irradiation conditions in the presence of chlorotrimethylsilane
(Scheme 1D).9 Furthermore, cyanated oxiranes were used with
phenylhydrazine in the presence of p-toluenesulfonic acid
without any metal complexes, reported by Xu et al. (Scheme
1E).10 In addition, transition-metal-catalyzed synthesis of
indoles via C−H bond activation was recently investigated
using anilines and azobenzenes as starting materials treated
with alkenes and alkynes.11,12 Despite these successful
achievements, a more efficient metal-free synthesis of indoles
from easily available starting materials under neutral conditions
is highly desired for expanding the library of substituted
indoles.13
Recently, we found that bis(neopentylglycolato)diboron
(B2nep2) served as a reductant for not only nitroarenes but
also for azobenzene in the presence of a catalytic amount of
4,4′-bipyridyl, in which N,O-diborylated hydroxyanilines and
N,N′-diborylated diphenylhydrazines were, respectively, gen-
erated as the initial reaction intermediates.14 Herein, we report
the metal-free synthesis of multisubstituted indoles 3 under
neutral reaction conditions by treating readily available
azoarenes 1 and ketones 2 with B2nep2 in the presence of a
catalytic amount of 4,4′-bipyridyl (Scheme 1F), in which N,N′-
diborylated diphenylhydrazines 5 and N-vinyl-1,2-diarylhydra-
zines 7 were the key intermediates. The mild reaction
conditions enabled us to synthesize diverse indole derivatives
bearing both electron-donating and electron-withdrawing
substituents, as well as N- and O-protecting groups.
3288
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
and B2cat2, giving diborylated diphenylhydrazine, proceeded
effectively but further reactions with 2a were slow. The origin
of the different reactivities of the in situ generated diborylated
diphenylhydrazine is unclear, but a similar substituent effect on
the boron atom was observed for the reduction of nitro-
arenes.14 This reaction proceeded in other polar solvents, such
as acetonitrile and THF, to produce 3aa in good yields (entries
10 and 11). Under the optimized conditions in entry 1, the
reaction could be scaled up to 1 mmol in toluene under stirring
for 16 h to give 3aa in a good isolated yield (entry 12).
Interestingly, a further oxidized starting material, azoxybenzene
(1a−O), was applicable with 3.3 equiv of B2nep2 under the
same reaction conditions, giving indole 3aa in an excellent
yield (entry 13, vide infra for conversion of azoxyarenes).
Although diboron compounds are known as deoxygenating
reagents of amine N-oxides,15 no reduction of azoxybenzene
1a-O to azobenzene 1a occurred in the absence of 4,4′-
bipyridyl, indicating that the deoxygenation of azoxybenzene
1a-O to azobenzene 1a is also a catalytic process. Such
deoxygenation of azoxybenzene is advantageous because
azoxyarenes are often coproduced during the synthesis of
azoarenes.16
RESULTS AND DISCUSSION
■
4,4′-Bipyridyl-Catalyzed Indole Synthesis. We began
our search for the best reaction conditions by preparing indole
3aa from azobenzene 1a and cyclohexanone 2a in the presence
of 2.2 equiv of B2nep2 and catalytic amounts of 4,4′-bipyridyl
(4 mol %). The mixture of 1a and 2.0 equiv of 2a was heated
at 100 °C in C6D6 for 24 h, and we obtained 3aa in 95% yield
(Table 1, entry 1). Under the reaction conditions, ketimine
Table 1. Optimization of Reaction Conditions for the
a
Indole Synthesis
2a
(equiv)
conv.
b
3aa
b
entry
diboron (equiv)
solvent
(%)
(%)
Substrate Scope. With the optimized reaction conditions
in hand, we evaluated the substrate scope and limitations of
ketones 2 (Table 2). Various cyclic ketones were applicable for
this indole formation to afford 3ab−ad in a good to excellent
yield, though a higher reaction temperature (120 °C) was
necessary for obtaining higher yields of 3ac and 3ad, the latter
of which is a precursor of the antidepressant drug, iprindole.9a
For 6-membered cyclic derivatives, a bulky tert-butyl
substituent at the 4-position 2e afforded 3ae in high yield,
and cyclohexanone 2l with a carbonyl protection at the 4-
position afforded the corresponding indole 3al in an excellent
yield. Most common N-protected 4-piperidone derivatives
were applicable with an excellent protection group tolerance:
in fact, indole formation with N-acetyl (Ac, 2f), N-benzoyl (Bz,
2g), N-tert-butyloxycarbonyl (Boc, 2h), N-carbobenzyloxy
(Cbz, 2i), N-benzyl (Bn, 2j), and N-toluenesulfonyl (Ts, 2k)
substituted 4-piperidones afforded the corresponding indoles
3af−3ak in good to excellent yields without the degradation of
the protecting groups, indicating that amide and carbamate
were intact under the reaction conditions, though general
Fischer indolization conditions starting from phenylhydrazine
are much less functional group tolerant.5,17 Cyclic aryl ketones
such as α-tetralone (2n) gave 3an in moderate yields.
Interestingly, β-tetralone (2m) gave exclusively 3am in a
moderate yield; this result differs from the previous Fischer
indole synthesis, where a mixture of indole isomers are
obtained.5e Ketones bearing an heteroarene such as 6,7-
dihydro-4(5H)-benzofuranone (2o) and 6,7-dihydro-4-benzo-
[b]thiophenone (2p) gave the respective indoles 3ao and 3ap
in moderate yields. Interestingly, unsymmetrical ketones such
as 2-butanone (2q) and 5-hexene-2-one (2r) gave 3aq and 3ar
in good yields without any other isomers. The reaction with
methyl 4-oxopentanoate (2t) also yielded one regioisomer 3at
in a good yield with the ester moiety intact (120 °C, 48 h).
We next investigated azoarenes with electron-donating and
electron-withdrawing substituents at the para-position (Table
3). Electron-rich azoarene 1b gave the corresponding indole
3ba in 60% yield. The azoarene 1c with p-methyl groups gave
the corresponding indole 3ca in good yield. Electron-deficient
para-substituted halogen-containing azoarenes 1d (p-Cl) and
1e (p-Br) gave indoles 3da and 3ea in good yields, whereas the
1
2
3
2.0
2.0
1.1
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
B2nep2, 2.2 equiv
B2nep2, 1.1 equiv
B2nep2, 2.2 equiv
B2nep2, 2.2 equiv
B2nep2, 2.2 equiv
B2nep2, 2.2 equiv
B2pin2, 2.2 equiv
B2cat2, 2.2 equiv
C6D6
C6D6
C6D6
C6D6
C6D6
C6D6
C6D6
C6D6
99
87
99
99
42
18
88
99
14
99
99
99
99
95 (88)
68
78
92
40
<5
34
25
N.D.
87
c
4
d
5
e
6
7
8
9
10
11
B2(OH)4, 2.2 equiv C6D6
B2nep2, 2.2 equiv
B2nep2, 2.2 equiv
B2nep2, 2.2 equiv
B2nep2, 3.3 equiv
CD3CN
THF-d8
toluene
C6D6
78
(80)
92
f
12
13
g
a
Standard reaction conditions: 1a (0.20 mmol), cyclohexanone 2a
(0.22 or 0.40 mmol, 1.1 or 2.0 equiv), B2nep2 (0.22 or 0.44 mmol, 1.1
or 2.2 equiv), 4,4′-bipyridyl (0.0080 mmol, 4.0 mol%), and solvent
(0.40 mL) under an argon atmosphere in a J-young NMR tube at 100
b
°C for 24 h. N.D. = not detected. 1H NMR yield based on the molar
amount of 1a using 1,3,5-trimethoxybenzene as the internal standard.
c
d
The isolated yield in parentheses. 4,4′-bipyridyl (2.0 mol%). 4,4′-
e
f
bipyridyl (1.0 mol%). Without 4,4′-bipyridyl. In 1 mmol scale
g
reaction. Azoxybenzene 1a−O (0.20 mmol) was used instead of 1a.
4aa derived from the condensation reaction of the in situ-
generated aniline and cyclohexanone 2a was detected. When
the amounts of 2a and B2nep2 were reduced to 1.1 equiv, the
yield of 3aa was decreased (entries 2 and 3). Decreasing the
catalyst loading of 4,4′-bipyridyl to 2 mol % had no significant
effect on the yield of 3aa, but the yield of 3aa was low under 1
mol% catalyst loading (entries 4 and 5). In the absence of 4,4′-
bipyridyl, 3aa was observed in only a small amount (entry 6).
When other diborons, such as B2pin2, B2cat2, and B2(OH)4,
were used instead of B2nep2 under the same reaction
conditions, 3aa was obtained in yields of only 34, 25, and
0%, respectively (entries 7−9). High conversion of 1a in
entries 7 and 8 indicated that the reduction of 1a with B2pin2
3289
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Several unsymmetrical azoarenes bearing one phenyl group
and one aryl group with p-MeO (1j), p-Me (1k), p-Cl (1l),
and p-CF3 (1m) substituents, were tested for the indole
synthesis (Scheme 2). In the case of electron-donating groups
(1j, 1k), we found the preferential formation of indole 3aa
over the substituted indoles (3ba, 3ca): for the methoxy group,
the 3aa:3ba ratio was 1.6:1, while for methyl group, 3aa:3ca
was 1.1:1. On the other hand, the preferential formation of 5-
substituted indoles (3da, 3fa) with electron-withdrawing
substituents over 3aa was observed. These observations
suggested that the electron-rich nitrogen atom of the azoarenes
was more reactive toward the carbonyl moiety of 2a to form
the N-alkenyl intermediate prior to the indole product 3 (vide
infra).
Table 2. Scope of Ketones
Mechanism. We conducted some controlled experiments
to elucidate the possible reaction mechanism. First, in the
absence of ketone 2, azobenzene 1a (2 mmol) reacts with
B2nep2 (1.2 equiv) in the presence of catalytic amounts of 4,4′-
bipyridyl (4 mol%) to give N,N′-bis[(neopentylglycolato)-
boryl]-1,2-diphenylhydrazine (5) in 90% yield via the boryl
group transfer from in situ-generated N,N′-bis[(neopentyl-
glycolato)boryl]-4,4′-bipyridinylidene18 (Scheme 3A). Metal-
free diborylation of azobenzene using diborons and hetero-
aromatic compounds as organocatalysts was reported by Zhu
and Li et al. and Caulton et al., respectively.19 Then, compound
5 was treated with 2a (2 equiv) in the absence of 4,4′-bipyridyl
and B2nep2, giving 3aa in good yield (89%) along with 1 equiv
of O(Bnep)2, PhNH2 (20%), and ketimine 4aa (67%) after 24
h (Scheme 3B). When B2nep2 (1.1 equiv) was added to the
mixture of 5 and 2a, 3aa was observed in 70% yield just after 2
h along with 26% of N,N′-diphenylhydrazine (6) and 44% of
4aa (Scheme 3C), in which B2nep2 served as a Lewis acid to
accelerate the overall reaction. In fact, when the same reaction
was carried out at 50 °C for 16 h, the key reaction
intermediate, enamine 7, was observed in 54% yield together
with 3aa (10%), 4aa (10%), and 6 (33%) (Scheme 3D).
Further heating of the reaction mixture at 100 °C for 2 h
resulted in the formation of 3aa in 64% yield without apparent
consumption of 6, which was clear proof for the involvement
of 7 as the key indole formation intermediate.
a
Standard reaction conditions: 1a (0.20 mmol), ketone 2 (0.40
mmol), B2nep2 (0.44 mmol, 2.2 equiv), and 4,4′-bipyridyl (0.0080
mmol, 4.0 mol%) in C6D6 (0.40 mL) under an argon atmosphere in a
J-young NMR tube at 100 °C for 24 h. Isolated yield is given in Table
2. Ketone 2 (0.80 mmol, 4.0 equiv), toluene (0.40 mL), 100 °C for 2
h then 120 °C for 22 h. 1a (1.0 mmol), ketone 2 (3.0 mmol, 3
equiv), B2nep2 (2.2 mmol, 2.2 equiv), and 4,4′-bipyridyl (0.040 mmol,
4.0 mol%) in toluene (2.0 mL) under an argon atmosphere in a J-
young Schlenk at 120 °C for 48 h.
b
We gained more insights into the reaction mechanism by
c
1
monitoring the reaction progress with H NMR measurement
(Figure 1). Under the optimized reaction conditions, 60% of
1a is consumed within 1 h, forming 3aa along 6 and 7 in 22,
23, and 15% yields, respectively, and all of 1a and 7 were
consumed within 2 h, generating 3aa and 6 in 60 and 40%
yields, respectively. After that time, the formation of 3aa was
very slow, but its yield increased with the slow consumption of
6: after 24 h, the yield of 3aa increased up to 95%. In fact, the
reaction of 6 with 2a in C6D6 for 24 h at 100 °C afforded 3aa
in 33% yield, and in the presence of B2nep2 (1.1 equiv), the
reaction rate improved to 60% of 3aa after 24 h (eq 2),
indicating that both 1a and 6 serve as starting materials for the
indole formation, but the rate of the reaction is much slower
starting from 6.
more electron-poor compounds 1f (p-CF3) and 1g (p-CN)
gave only 48% of 3fa and 46% of 3ga, respectively, along with
nearly 50% of 4,4′-disubstituted-1,2-diarenehydrazine as the
major side products. Azoarene 1h bearing a tert-butyldime-
thylsiloxy group gave the respective indole 3ha in an excellent
yield without any deprotection of the silyl group. The steric
hindrance around the N=N bond plays an important role in
this system because ortho-methylated azoarene 1i gave 19% of
8-methyl indole 3ia.
Azoxyarenes were also suitable for the present trans-
formation under similar conditions with 3.3 equiv of B2nep2
to give the corresponding indole 3aa in an excellent yield
(Table 4). A series of azoxyarenes bearing electron-donating
and electron-withdrawing groups at the para-position were
examined, and yields similar to those of the corresponding
azoarenes were obtained with p-Me (3ca, 81%), p-Cl (3da,
87%), and p-Br (3ea, 86%) substituents, respectively.
3290
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Table 3. Scope of Azoarenes
a
Standard reaction conditions: 1 (0.20 mmol), cyclohexanone 2a (0.40 mmol), B2nep2 (0.44 mmol, 2.2 equiv), and 4,4′-bipyridyl (0.0080 mmol, 4
mol%) in C6D6 (0.40 mL), under an argon atmosphere in a J-young NMR tube at 100 °C for 24 h. Isolated yield is given in Table 3.
a
4,4′-bipyridinylidene (I) from 4,4′-bipyridyl and B2nep2,
producing diborylated N,N′-diphenylhydrazine (5). Step 2 is
the reaction of 5 with 2a, giving enamine 7 and O(Bnep)2. A
similar enamine intermediate was proposed by Knochel et al.
for indole formation from azobenzene and cyclohexenylmag-
nesium iodide.9a During the enamine formation, the
nucleophilic attack of the nitrogen atom of 5 to the carbonyl
moiety of 2a is the key C−N bond-forming step for generating
intermediate II, where the electron-rich nitrogen atom
preferentially reacts with the carbonyl moiety, as shown in
Scheme 2. The direct observation of the C−N bond-forming
product was unsuccessful, but bis(hemiaminal) compound 8
was successfully isolated upon the addition of benzaldehyde to
5 (eq 3). The elimination of HOBnep from II generates
reactive species III, which is easily quenched by HOBnep to
form the experimentally observed intermediate 7 and
O(Bnep)2. Finally, the formation of indole derivative 3aa
from 7 smoothly proceeds with the elimination of 1.0 equiv of
aniline by essentially the same mechanism as the well-
established Fischer indole formation.
Table 4. Scope of Azoxyarenes
a
Standard reaction conditions: 1-O (0.20 mmol), cyclohexanone 2a
(0.40 mmol), B2nep2 (0.66 mmol, 3.3 equiv), and 4,4′-bipyridyl
(0.0080 mmol, 4 mol%) in C6D6 (0.40 mL), under an argon
atmosphere in a J-young NMR tube at 100 °C for 24 h. Yield was
1
determined by H NMR with respect to the internal standard.
The competitive reactions of equimolar amounts of
symmetric para-substituted azoarenes bearing electron-donat-
ing (1b, R = OMe; 1c, R = Me) and electron-withdrawing
According to the control experiments, the plausible reaction
mechanism is depicted in Scheme 4. In step 1, diborylation of
azobenzene (1a) proceeds by in situ-generated N,N′-diboryl-
Scheme 2. Reactivity of Unsymmetrical Azoarenes with Different Electronic Substituents
3291
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 3. Control Experiments
Scheme 4. Reaction Mechanism for the Indole Formation
groups (1d, R = Cl; 1f, R = CF3) against azobenzene 1a were
also studied for checking the initial reaction rate in 10 min
(Scheme 5). The results clearly indicated that the consumption
of azoarenes by the diborylated species is accelerated by
electron-withdrawing groups, whereas the indole formation via
intermediate 7 was much faster for diborylated intermediates
having electron-donating groups.
Gram-Scale Reaction. In order to demonstrate the
potential applicability of this protocol, a large-scale synthesis
was exemplified for 2,8-dimethyltetrahydro-γ-carboline 3cv, a
precursor of Dimebon, an anti-histamine drug,20 from 1,2-
1
Figure 1. Monitoring the reaction with H NMR. Standard reaction
condition: 1a (0.20 mmol), cyclohexanone 2a (0.40 mmol, 2.0 equiv),
B2nep2 (0.44 mmol, 2.2 equiv), 4,4′-bipyridyl (0.008 mmol, 4.0 mol
%), C6D6 (0.40 mL), under an argon atmosphere, in a J-young NMR
tube, 100 °C. Each unit in the X-axis (time) represents a different
reaction setup. 1H NMR yield using 1,3,5-trimethoxybenzene (TMB)
as the internal standard.
3292
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 5. Competing Reactions 1a vs 1b, 1c, 1d, and 1f
Scheme 6. Two-Step One-Pot Synthesis of 3cv in a 10 mmol Scale
bis(p-tolyl)diazene 1c and N-methyl-4-piperidone 2v (Scheme
6). By using ketone 2v with the scale-up conditions, the two-
step one-pot sequences, as shown in Scheme 6, are appropriate
to obtain the final product 3cv in a better yield: the catalytic
borylation of 1c by B2nep2 in toluene for 5 h afforded 5c, to
yield. Further studies using the metal-free reductive catalytic
system 4,4′-bipyridyl/diboron are ongoing in our laboratory to
expand the synthetic utility in metal-free organic trans-
formations.
which ketone 2v was added and continuous heating for 24 h
gave 3cv in 72% yield (1.44 g) with the recovery of excess
B2nep2 (2.2 g) from the reaction mixture.
EXPERIMENTAL SECTION
■
General Experimental Details. All reactions were performed
under an argon atmosphere using an argon-filled glovebox. All
diboranes bis(neopentylglycolato)diboron (B2nep2), bis(pinacolato)-
diboron (B2pin2), bis(catecholato)diboron (B2cat2), and tetrahydrox-
ydiboron (B2(OH)4) were purchased and used as received.
Azobenzene 1a, azoxybenzene 1a−O, and ketones 2a−2u were
purchased and used as received. Azoarenes 1b−i were prepared
according to the published procedure.16 Azoarenes 1i−1m were
prepared by using the Mills reaction conditions.21 Azoxyarenes 1c−e-
O were prepared according to the literature.16 N-Methyl-4-piperidone
2v was dried over CaH2 and purified by vacuum distillation.
Anhydrous solvents (toluene, THF, and acetonitrile) were purchased
from Kanto Chemical and further purified by passing through
activated alumina under positive argon pressure using Grubbs column
(Glass Counter Solvent Dispending System, Nikko Hansen & Co.,
Ltd.). For NMR analyses CDCl3 and DMSO-d6 were used as received.
For monitoring reactions under argon C6D6 and CD3CN were
purified by distillation (trap to trap) over CaH2 and stored inside the
glovebox. NMR-spectra [1H at 400 MHz, 13C{1H} at 100 MHz, 11B at
128 MHz] were recorded on a BRUKER AVANCE III 400 MHz
spectrometer. Chemical shifts (δ values) were reported in parts per
CONCLUSIONS
■
In summary, we developed 4,4′-bipyridyl-catalyzed indoliza-
tion of azoarenes 1 with ketones 2 with bis(neopentyl
glycolato)diboron as a reductant under neutral conditions
following the Fischer indole synthesis mechanism. The key
intermediate, N,N′-diboryl-1,2-diarylhydrazines 5, reacts with
ketones to form N-ene-1,2-diphenylhydrazines 7 and O-
(Bnep)2, and 7 rearranges to form indole 3. This catalytic
system is regioselective toward asymmetric methyl alkyl
ketones. In addition, the reaction conditions are tolerant
toward various N-protecting groups such as Boc, Cbz, Ac, Bz,
Bn, and Ts, as well as carbonyl-protecting group (ketal) and O-
protecting groups (TBS). Azoxyarene derivatives 1-O can also
be used under the optimized reaction conditions with 3.3 equiv
of B2nep2 to obtain the respective indoles 3. The present
catalytic system can be applicable in gram-scale with good
3293
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
million (ppm) with CDCl3, CD3CN, C6D6, and DMSO-d6. In 1H and
13C NMR spectra, coupling constants are reported in Hz, and
multiplicity was indicated as follows: s (singlet); d (doublet); t
(triplet); q (quartet); quint (quintet); m (multiplet); dd (doublet of
doublets); and tt (triplet of triplets). Tetramethylsilane (0 ppm) or
the residual solvent peak are used as a reference, 7.26 ppm for CDCl3,
1.94 ppm for CD3CN, 7.16 ppm for C6D6, and 2.50 ppm for DMSO-
d6. In 13C NMR spectra, the residual solvent peak used as a reference
is 77.16 ppm for CDCl3, 118.26 ppm for CD3CN, 128.06 ppm for
C6D6, and 39.52 ppm for DMSO-d6. GC−MS Spectra were obtained
on Shimadzu GCMS-QP2010. High-resolution mass spectra were
obtained on JEOL JMS 700 (double-focusing mass spectrometer).
Flash column chromatography was performed by using silica gel 60
(0.040−0.0663 nm, 230−400 mesh ASTM).
Preparation of 3ac. The reaction was performed following the
general procedure (modification 1). 1H NMR yield: 90%. The residue
was purified by flash column chromatography (silica gel, hexane/ethyl
acetate 10:1, v/v) to give the product as a white solid. Yield: 32 mg,
86%. 1H NMR (400 MHz, CDCl3): δ 7.66 (br s, 1H), 7.52−7.43 (m,
1H), 7.30−7.21 (m, 1H), 7.13−7.02 (m, 2H), 2.83 (dd, J = 11.6, 5.9
Hz, 4H), 1.93−1.88 (m, 2H), 1.84−1.73 (m, 4H). 13C{1H} NMR
(100 MHz, CDCl3): δ 137.5, 134.4, 129.4, 120.8, 119.2, 117.8, 113.9,
110.3, 31.9, 29.7, 28.9, 27.7, 24.8. The NMR data were consistent
with the reported data.17a
Preparation of 3ad. The reaction was performed following the
general procedure (modification 1). 1H NMR yield: 72%. The residue
was purified by flash column chromatography (silica gel, hexane/ethyl
acetate 10:1, v/v) to give the product as a white solid. Yield: 26 mg,
65%. 1H NMR (400 MHz, CDCl3): δ 7.67 (br s, 1H), 7.56−7.45 (m,
1H), 7.28 (d, J = 7.0 Hz, 1H), 7.09 (q, J = 7.1 Hz, 2H), 2.86 (dd, J =
12.4, 5.9 Hz, 4H), 1.83−1.69 (m, 4H), 1.52−1.37 (m, 4H). 13C{1H}
NMR (100 MHz, CDCl3): δ 135.5, 135.1, 128.7, 120.6, 118.9, 117.7,
111.7, 110.2, 29.6, 29.5, 26.1, 25.9, 22.2. The NMR data were
consistent with the reported data.17a
General Procedure for Indole Synthesis. Inside a glovebox in
an oven-dried J-young NMR tube, bis(neopentylglycolato)diboron
(B2nep2, 0.44 mmol, 100 mg), azobenzene (1a, 0.20 mmol, 36.5 mg),
cyclohexanone (2a, 0.40 mmol, 42 μL), 4,4′-bipyridyl (0.0080 mmol,
1.25 mg), and C6D6 (0.40 mL) were added. The reaction mixture was
heated at 100 °C for 24 h. During the first 10 min in order to dissolve
all the solids, the tube was gently placed upside down (once or twice)
and put it back at a 100 °C bath. After the reaction time, the tube was
left for cooling to ambient temperature. The solution was filtered
through celite into a round-bottom flask and the tube was washed
with ethyl acetate (2−3 mL), then the solvent was evaporated. At this
point, for NMR analyses, the internal standard (TMB or CH2Br2) was
added followed by the corresponding deuterated solvent. For
isolation, product 3 was purified by column chromatography using
hexane/ethyl acetate as an eluent. Modification 1: for the preparation
of indoles 3ac and 3ad, 0.80 mmol (4.0 equiv) of ketones 2c and 2d
were used in toluene (0.4 mL), and heated at 100 °C for 2 h, then at
120 °C for 22 h. Modification 2: for the preparation of indole 3aq,
3ar, and 3as (in 1 mmol scale), the reaction was carried out in toluene
(2.0 mL) and heated at 120 °C for 48 h.
Preparation of 3ae. The reaction was performed following the
1
general procedure. H NMR yield: 95%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 10:1, v/
1
v) to give the product as a white solid. Yield: 42 mg, 92%. H NMR
(400 MHz, CDCl3): δ 7.65 (br s, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.27
(d, J = 8.8 Hz, 1H), 7.17−7.04 (m, 2H), 2.88−2.72 (m, 3H), 2.47−
2.35 (m, 1H), 2.16−2.06 (m, 1H), 1.57−1.50 (m, 2H), 1.01 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3): δ 136.3, 134.3, 128.2, 121.1,
119.2, 117.8, 110.8, 110.5, 45.6, 32.8, 27.7, 24.9, 24.3, 22.4. The NMR
data were consistent with the reported data.23
Preparation of 3af. The reaction was performed following the
1
general procedure. H NMR yield: 84%. The residue was purified by
flash column chromatography (silica gel, ethyl acetate) to give the
product as a white solid. Yield: 35 mg, 82%. NMR analyses showed a
mix of two rotamers in a ratio 1.3:1 [rotamer 1 (R1):rotamer 2 (R2)].
1H NMR (400 MHz, DMSO-d6): δ 10.88 (R2, br s, 1H), 10.86 (R1,
br s, 1H), 7.40 (R1/R2, t, J = 7.5 Hz, 2H), 7.29 (R1/R2, d, J = 7.8 Hz,
2H), 7.03 (R1/R2, dd, J = 11.1, 7.2 Hz, 2H), 6.96 (R1/R2, dd, J =
13.3, 6.5 Hz, 2H), 4.64 (R2, s, 2H), 4.62 (R1, s, 2H), 3.84 (R2, t, J =
5.7 Hz, 2H), 3.77 (R1, t, J = 5.6 Hz, 2H), 2.86 (R1, t, J = 5.3 Hz, 2H),
2.75 (R2, t, J = 5.5 Hz, 2H), 2.13 (R1, s, 3H), 2.12 (R2, s, 3H).
13C{1H} NMR (100 MHz, DMSO-d6): δ 169.1 (R2), 168.7 (R1),
135.9 (R2), 135.8 (R1), 132.9 (R2), 132.3 (R1), 125.3 (R1), 125.0
(R2), 120.6 (R2), 120.6 (R1), 118.5 (R1), 118.4 (R2), 117.2 (R2),
117.1 (R1), 110.9 (R2), 110.9 (R1), 105.8 (R1), 105.5 (R2), 43.4
(R1), 42.9 (R2), 38.7 (R1), 38.5 (R2), 23.6 (R1), 22.8 (R2), 21.9
(R2), 21.5 (R1). The NMR data were consistent with the reported
data.24
Preparation of 3aa. The reaction was performed following the
1
general procedure. H NMR yield: 95%. the residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 10:1, v/
1
v) to give the product as a white solid. Yield: 30 mg, 88%. H NMR
(400 MHz, CDCl3): δ 7.65 (br s, 1H), 7.45 (d, J = 7.6 Hz, 1H),
7.28−7.26 (m, 1H), 7.12−7.04 (m, 2H), 2.74−2.70 (m, 4H), 1.93−
1.86 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 135.8, 134.2,
128.0, 121.1, 119.2, 117.9, 110.5, 110.3, 23.4, 23.4, 23.4, 21.1. The
NMR data were consistent with the reported data.22 When we applied
this indole formation under air, the yield was dropped to 74% and 1,2-
diphenylhydrazine remained in the reaction mixture, though 1a was
consumed over 90%.
1 mmol Scale Reaction for 3aa. In an oven-dried J-young Schlenk
(20 mL) containing a magnetic stirring bar, 1a (1.00 mmol, 182.2
mg), 2a (2.00 mmol, 210 μL), B2nep2 (2.20 mmol, 500 mg), 4,4′-
bipyridyl (0.04 mmol, 6.2 mg), and toluene (1.0 mL) were added.
The reaction was heated at 100 °C for 16 h. After that time and after
reaching ambient temperature, the solvent was evaporated under
reduced pressure and the residue was purified by flash column
chromatography (silica gel, hexane/ethyl acetate 10:1, v/v) to give the
product as a white solid. Yield: 137 mg, 80%. When a standard
Schlenk flask equipped with a reflux condenser was used for the
reaction under an Ar atomsphere in toluene, we found the formation
of 3aa in 82% yield. For quick monitoring of the reaction progress, we
used C6D6 as the solvent in our trials, but all the reactions were
essentially replaceable to toluene in standard Schlenk flask conditions.
Preparation of 3ab. The reaction was performed following the
Preparation of 3ag. The reaction was performed following the
1
general procedure. H NMR yield: 97%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 1:1, v/
v) to give the product as a white solid. Yield: 49 mg, 89%. NMR
analyses showed a mix of two rotamers in a ratio 1.2:1 [rotamer 1
(R1):rotamer 2 (R2)]. 1H NMR (400 MHz, CDCl3): δ 8.07 (R1/R2,
br s, 2H), 7.47−7.44 (R1/R2, m, 12H), 7.31−7.29 (R1/R2, m, 2H),
7.14−7.04 (R1/R2, m, 4H), 4.97 (R2, s, 2H), 4.66 (R1, s, 2H), 4.16
(R1, s, 2H), 3.76 (R2, s, 2H), 2.96 (R1, s, 2H), 2.87 (R2, s, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 171.4 (R1), 171.4 (R2), 136.2
(R1), 136.1 (R2), 132.7, 130.0, 128.7, 127.3, 127.0, 125.3, 122.0,
119.8, 117.5, 111.0, 107.2, 45.7 (R1), 45.3 (R2), 40.5 (R1), 40.4
(R2), 24.5 (R2), 23.4 (R1). The NMR data were consistent with the
reported data.25
1
general procedure. H NMR yield: 84%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 10:1, v/
v) to give the product as a white solid. Yield: 25 mg, 80%. H NMR
Preparation of 3ah. The reaction was performed following the
general procedure. H NMR yield: 96%. The residue was purified by
1
1
(400 MHz, CDCl3): δ 7.81 (br s, 1H), 7.44−7.42 (m, 1H), 7.31−7.29
(m, 1H), 7.09−7.07 (m, 2H), 2.89−2.82 (m, 4H), 2.58−2.51 (m,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ 143.8, 141.2, 124.9, 120.6,
120.0, 119.6, 118.6, 111.4, 28.8, 26.0, 24.6. The NMR data were
consistent with the reported data.17a
flash column chromatography (silica gel, hexane/ethyl acetate 5:1, v/
v) to give the product as colorless oil. Yield: 49 mg, 90%. H NMR
(400 MHz, CDCl3): δ 7.85 (s, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.31 (d,
J = 7.8 Hz, 1H), 7.16 (t, J = 7.3 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H),
4.65 (s, 2H), 3.82 (s, 2H), 2.83 (s, 2H), 1.51 (s, 9H). 13C{1H} NMR
1
3294
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(100 MHz, CDCl3): δ 155.4, 136.1, 132.2, 125.8, 121.8, 119.7, 117.7,
110.8, 107.8, 80.0, 41.3, 40.9, 28.7, 28.5, 23.7. The NMR data were
consistent with the reported data.26
chromatography (silica gel, hexane/ethyl acetate 20:1, v/v) to give
the product as a white solid. Yield: 18 mg, 43%. 1H NMR (400 MHz,
CDCl3): δ 8.02 (br s, 1H), 7.48−7.45 (m, 1H), 7.36 (d, J = 0.9 Hz,
1H), 7.35−7.32 (m, 1H), 7.13−7.08 (m, 2H), 6.51 (d, J = 1.5 Hz,
1H), 3.18−3.14 (m, 2H), 3.09−3.04 (m, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ 154.1, 141.8, 136.4, 130.2, 127.6, 120.8, 120.1,
117.9, 112.8, 111.1, 106.0, 105.0, 22.8, 20.3. GC−MS (EI) m/z
(relative intensity): 209 (M+, 100), 189 (M+ − CHO, 85). HRMS
(FAB) m/z: [M+] calcd for C14H11NO, 209.0841; found, 209.0841.
Preparation of 3ap. The reaction was performed following the
Preparation of 3ai. The reaction was performed following the
1
general procedure. H NMR yield: 88%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 5:1, v/
v) to give the product as colorless liquid. Yield: 48 mg, 79%. 1H NMR
(400 MHz, CDCl3): δ 7.94 (br s, 1H), 7.46−7.30 (m, 7H), 7.19−7.09
(m, 2H), 5.22 (s, 2H), 4.75 (s, 2H), 3.91 (s, 2H), 2.84 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3): δ 156.1, 136.9, 136.0, 132.1,
131.5, 128.7, 128.2, 128.1, 121.8, 119.8, 117.7, 110.9, 107.3, 67.4,
41.6, 23.8, 23.5. The NMR data were consistent with the reported
data.17a
1
general procedure. H NMR yield: 40%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 40:1, v/
1
v) to give the product as a white solid. Yield: 16 mg, 36%. H NMR
(400 MHz, CDCl3): δ 8.07 (br s, 1H), 7.54−7.52 (m, 1H), 7.37−7.35
(m, 1H), 7.18−1.12 (m, 4H), 3.17−3.07 (m, 4H). 13C{1H} NMR
(100 MHz, CDCl3): δ 136.9, 136.2, 131.6, 129.6, 127.6, 123.0, 121.6,
120.8, 120.1, 118.4, 111.2, 108.4, 24.8, 20.8. GC−MS (EI) m/z
(relative intensity): 225 (M+, 92), 224 (M+ − H, 100), 180 (M+ −
CHS, 15). HRMS (FAB) m/z: [M+] calcd for C14H11NS, 225.0612;
found, 225.0615.
Preparation of 3aq. The reaction was performed following the
general procedure (modification 2). 1H NMR yield: 88%. The residue
was purified by flash column chromatography (silica gel, hexane/ethyl
acetate 20:1, v/v) to give the product as a white solid. Yield: 117 mg,
80%. 1H NMR (400 MHz, CDCl3): δ 7.65 (br s, 1H), 7.47 (d, J = 7.2
Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.15−7.04 (m, 2H), 2.37 (s, 3H),
2.23 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 135.4, 130.7,
129.6, 121.0, 119.2, 118.1, 110.1, 107.3, 11.7, 8.6. The NMR data
were consistent with the reported data.17a
Preparation of 3aj. The reaction was performed following the
general procedure. H NMR yield: 78%. The residue was purified by
1
flash column chromatography (silica gel, hexane/ethyl acetate 1:2, v/
1
v) to give the product as a white solid. Yield: 40 mg, 76%. H NMR
(400 MHz, CDCl3): δ 7.83 (s, 1H), 7.42 (d, J = 7.1 Hz, 2H), 7.36−
7.32 (m, 3H), 7.29−7.23 (m, 2H), 7.13−7.06 (m, 1H), 7.06−7.00
(m, 1H), 3.80 (s, 2H), 3.74 (s, 2H), 2.90−2.87 (m,2H), 2.82−2.79
(m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 138.6, 136.2, 132.2,
129.3, 128.5, 127.3, 126.3, 121.3, 119.4, 117.7, 110.7, 108.8, 62.4,
50.2, 49.9, 23.8. The NMR data were consistent with the reported
data.27
Preparation of 3ak. The reaction was performed following the
1
general procedure. H NMR yield: 99%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 5:1, v/
1
v) to give the product as a white solid. Yield: 60 mg, 92%. H NMR
(400 MHz, CDCl3): δ 7.79 (br s, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.39
(d, J = 7.7 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.17−7.13 (m, 2H),
7.12−7.07 (m, 2H), 4.40 (s, 2H), 3.54 (t, J = 5.7 Hz, 2H), 2.88 (t, J =
5.7 Hz, 2H), 2.41 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
143.7, 136.1, 134.5, 131.0, 129.8, 127.7, 125.6, 122.0, 119.9, 117.7,
110.9, 106.4, 43.6, 43.2, 23.8, 21.6. The NMR data were consistent
with the reported data.25
Preparation of 3ar. The reaction was performed following the
1
general procedure. H NMR yield: 78%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 30:1, v/
1
v) to give the product as colorless oil. Yield: 118 mg, 69%. H NMR
(400 MHz, CDCl3): δ 7.71 (br s, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.27
(d, J = 6.8 Hz, 1H), 7.13−7.06 (m, 2H), 5.99 (ddt, J = 16.2, 10.0, 6.1
Hz, 1H), 5.07 (dd, J = 17.0, 1.8 Hz, 1H), 5.00 (dd, J = 10.0, 1.6 Hz,
1H), 3.47 (d, J = 6.1 Hz, 2H), 2.37 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 137.5, 135.4, 131.3, 128.9, 121.1, 119.3, 118.4,
114.5, 110.2, 109.5, 28.7, 11.7. The NMR data were consistent with
the reported data.30
Preparation of 3al. The reaction was performed following the
1
general procedure. H NMR yield: 99%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 5:1, v/
1
v) to give the product as a white solid. Yield: 43 mg, 94%. H NMR
(400 MHz, CDCl3): δ 7.73 (br s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.26
(d, J = 7.7 Hz, 1H), 7.13−7.04 (m, 2H), 4.14−3.98 (m, 4H), 2.97 (s,
2H), 2.94 (t, J = 6.5 Hz, 2H), 2.09 (t, J = 6.5 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ 136.8, 132.5, 127.9, 121.5, 119.4, 117.8, 110.6,
109.3, 108.4, 64.8, 32.1, 32.0, 21.7. The NMR data were consistent
with the reported data.28
Preparation of 3as. The reaction was performed following the
1
general procedure. H NMR yield: 74%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 10:1, v/
1
v) to give the product as yellow oil. Yield: 140 mg, 65%. H NMR
(400 MHz, CDCl3): δ 7.85 (br s, 1H), 7.55 (d, J = 6.7 Hz, 1H),
7.26−7.24 (m, 1H), 7.14−7.08 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H),
3.68 (s, 2H), 2.40 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 172.2, 135.3, 132.8, 128.7, 121.3, 119.6, 118.2,
110.4, 104.8, 60.8, 30.6, 14.4, 11.8. The NMR data were consistent
with the reported data.31
Preparation of 3am. The reaction was performed following the
1
general procedure. H NMR yield: 54%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 10:1, v/
1
v) to give the product as a dark solid. Yield: 19 mg, 44%. H NMR
(400 MHz, CDCl3): δ 8.03 (d, J = 7.2 Hz, 1H), 7.99 (s, 1H), 7.86 (d,
J = 7.6 Hz, 1H), 7.36 (dd, J = 6.7, 1.9 Hz, 1H), 7.31 (t, J = 7.8 Hz,
1H), 7.25−7.16 (m, 3H), 7.09 (td, J = 7.4, 1.0 Hz, 1H), 3.11−3.04
(m, 2H), 3.00−2.93 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
137.3, 136.4, 134.0, 133.4, 128.1, 127.1, 125.1, 124.4, 122.4, 121.6,
120.7, 119.7, 111.2, 110.9, 29.7, 22.7. GC−MS (EI) m/z (relative
intensity): 219 (M+, 100). HRMS (FAB) m/z: [M+] calcd for
C16H13N, 219.1048; found, 219.1044.
Preparation of 3ba. The reaction was performed following the
general procedure. The residue was purified by flash column
chromatography (silica gel, hexane/ethyl acetate 20:1, v/v) to give
the product as a white solid. Yield: 24 mg, 60%. 1H NMR (400 MHz,
CDCl3): δ 7.54 (br s, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 2.3
Hz, 1H), 6.78 (dd, J = 8.7, 2.5 Hz. 1H), 3.87 (s, 3H), 2.73−2.67 (m,
4H), 1.93−1.87 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ
154.1, 135.2, 130.9, 128.4, 111.1, 110.7, 110.2, 100.5, 56.2, 23.5, 23.5,
23.4, 21.1. The NMR data were consistent with the reported data.23
Preparation of 3ca. The reaction was performed following the
Preparation of 3an. The reaction was performed following the
1
general procedure. H NMR yield: 50%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 10:1, v/
1
1
v) to give the product as a dark solid. Yield: 17 mg, 39%. H NMR
general procedure. H NMR yield: 88%. The residue was purified by
(400 MHz, CDCl3): δ 8.20 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.41−
7.37 (m, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.31−7.23 (m, 2H), 7.21−
7.15 (m, 2H), 7.14−7.10 (m, 1H), 3.10−3.06 (m, 2H), 3.01−2.97
(m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 137.2, 136.7, 133.2,
129.1, 128.7, 127.6, 126.9, 126.8, 122.5, 120.0, 119.9, 118.9, 112.9,
111.2, 29.7, 19.9. The NMR data were consistent with the reported
data.29
flash column chromatography (silica gel, hexane/ethyl acetate 10:1, v/
v) to give the product as a white solid. Yield: 30 mg, 81%. H NMR
1
(400 MHz, CDCl3): δ 7.53 (br s, 1H), 7.25 (s, 1H), 7.16 (d, J = 8.2
Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 2.75−2.65 (m, 4H), 2.45 (s, 3H),
1.97−1.82 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 134.4,
134.1, 128.4, 128.3, 122.5, 117.7, 110.1, 109.9, 23.5, 23.5, 23.4, 21.6,
21.1. The NMR data were consistent with the reported data.32
Preparation of 3da. The reaction was performed following the
Preparation of 3ao. The reaction was performed following the
general procedure. The residue was purified by flash column
1
general procedure. H NMR yield: 90%. The residue was purified by
3295
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
flash column chromatography (silica gel, hexane/ethyl acetate 20:1, v/
v) to give the product as a white solid. Yield: 35 mg, 80%. H NMR
temperature, the solvent was evaporated under reduced pressure, then
1
1
internal standard was added (CH2Br2) and H NMR was measured
(1H NMR yield: 88%). The residue was purified by flash column
(400 MHz, CDCl3): δ 7.67 (br s, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.17
(d, J = 8.5 Hz, 1H), 7.05 (dd, J = 8.5, 2.0 Hz, 1H), 2.72 (t, J = 5.9 Hz,
2H), 2.66 (t, J = 5.8 Hz, 2H), 1.97−1.80 (m, 4H). 13C{1H} NMR
(100 MHz, CDCl3): δ 135.9, 134.1, 129.2, 124.9, 121.2, 117.5, 111.3,
110.3, 23.4, 23.3, 23.2, 20.9. The NMR data were consistent with the
reported data.23
chromatography (silica gel, ethyl acetate then acetone) to give the
1
product as a white solid. Yield: 32 mg, 80%. H NMR (400 MHz,
CDCl3): δ 7.75 (br s, 1H), 7.19−7.15 (m, 2H), 6.94 (d, J = 8.2 Hz,
1H), 3.66 (s, 2H), 2.85−2.82 (m, 4H), 2.56 (s, 3H), 2.43 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 134.6, 132.0, 128.7, 126.5,
122.8, 117.5, 110.4, 108.5, 52.6, 51.9, 45.9, 24.0, 21.6. The NMR data
were consistent with the reported data.34 Preparation of 3cv in gram-
scale reaction: (step 1) in an oven-dried J-young Schlenk (100 mL)
containing a magnetic stirring bar, 1,2-bis(p-tolyl)diazene (1c, 10.0
mmol, 2.1 g), B2nep2 (22 mmol, 4.9 g), 4,4′-bipyridyl (0.40 mmol,
62.5 mg), and toluene (10 mL) were added. The reaction was heated
at 100 °C for 5 h (the color change from red to light yellow is a good
visual indication of the full borylation of the azoarene 1c, see pictures
below). (Step 2) After that time and after reaching ambient
temperature, N-methyl-4-piperidone 2v (20 mmol, 2.5 mL) was
added under inert conditions, and the reaction further heated at 100
°C for 24 h. After that time and after reaching ambient temperature,
the solvent was evaporated under reduced pressure and the residue
was purified by flash column chromatography (silica gel, 1hexane/
ethyl acetate 2:1, 2hexane/ethyl acetate 1:2 (B2nep2, 2.2 g), 3
ethyl acetate, 4acetone) to give the product as a white solid. Yield:
1.44 g, 72%.
Preparation of 3ea. The reaction was performed following the
1
general procedure. H NMR yield: 88%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 20:1, v/
1
v) to give the product as a white solid. Yield: 40 mg, 80%. H NMR
(400 MHz, CDCl3): δ 7.68 (br s, 1H), 7.57 (d, J = 1.4 Hz, 1H), 7.18
(dd, J = 8.5, 1.8 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 2.72 (t, J = 5.9 Hz,
2H), 2.66 (t, J = 5.8 Hz, 2H), 1.98−1.81 (m, 4H). 13C{1H} NMR
(100 MHz, CDCl3): δ 135.7, 134.4, 129.9, 123.8, 120.6, 112.5, 111.8,
110.2, 23.4, 23.3, 23.2, 20.9. The NMR data were consistent with the
reported data.33
Preparation of 3fa. The reaction was performed following the
1
general procedure. H NMR yield: 54%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 20:1, v/
1
v) to give the product as a white solid. Yield: 23 mg, 48%. H NMR
(400 MHz, CDCl3): δ 7.85 (br s, 1H), 7.74 (s, 1H), 7.39−7.29 (m,
2H), 2.80−2.67 (m, 4H), 1.95−1.87 (m, 4H). 13C{1H} NMR (100
MHz, CDCl3): δ 137.6, 136.1, 127.5, 125.7 (C−F, q, 1JCF = 271 Hz),
2
3
121.6 (C−F, q, JCF = 32 Hz), 117.9 (C−F, q, JCF = 4 Hz), 115.5
Time-Course Analyses of the Catalytic Reaction (Figure 1).
Inside a glovebox in an oven-dried J-young NMR tube, B2nep2 (0.44
mmol, 100 mg), 1a (0.20 mmol, 36.5 mg), 2a (0.40 mmol, 42 μL),
C6D6 (0.40 mL), and 4,4′-bipyridyl (0.0080 mmol, 1.25 mg) were
added. The reaction mixture was heated at 100 °C. During the first 10
min in order to dissolve all the solids, the tube was gently placed
upside down (once or twice) and put it back at 100 °C. After the
reaction time [1, 2, 3, 4, 5, 6, 16, and 24 h (each time corresponds to
the end of the reaction of 8 different reaction set-ups)], the tube was
left for cooling to an ambient temperature, then TMB was added, and
(C−F, q, JCF = 4 Hz), 111.3, 110.5, 23.4, 23.2, 23.2, 20.9. 19F{1H}
3
NMR (376 MHz, CDCl3): δ −60.1. The NMR data were consistent
with the reported data.33
Preparation of 3ga. The reaction was performed following the
1
general procedure. H NMR yield: 48%. The residue was purified by
flash column chromatography (silica gel, hexane/ethyl acetate 5:1, v/
1
v) to give the product as a white solid. Yield: 18 mg, 46%. H NMR
(400 MHz, CDCl3): δ 8.00 (br s, 1H), 7.78 (s, 1H), 7.36−7.29 (m,
2H), 2.75 (t, J = 5.9 Hz, 2H), 2.70 (t, J = 5.9 Hz, 2H), 1.98−1.84 (m,
4H). 13C{1H} NMR (100 MHz, CDCl3): δ 137.6, 136.7, 127.9, 124.4,
123.3, 121.2, 111.3, 111.1, 102.2, 23.3, 23.1, 23.0, 20.7. The NMR
data were consistent with the reported data.23
1
1H NMR was measured. All the H NMR spectra were shown in
Figure S1 in Supporting Information.
Diborylation of Azobenzene for Synthesizing 5 (Scheme
3A). Inside a glovebox in an oven-dried J-young Schlenk (20 mL)
containing a magnetic-stirring bar, B2nep2 (2.2 mmol, 500 mg), 1a
(2.00 mmol, 365 mg), 4,4′-bipyridyl (0.080 mmol, 12.5 mg), and
toluene (1.0 mL), were added. The reaction mixture was heated at
100 °C for 16 h. After the reaction time, the Schlenk was left for
cooling to ambient temperature. The solvent was evaporated under
vacuum, and the solid was washed with hexane (3 mL × 3) and
decanted. The white solid was dried under vacuum. No further
purification was needed for further control experiments. Yield: 0.734
g, 90%. 1H NMR (400 MHz, C6D6): δ 7.84 (d, J = 8.1 Hz, 4H), 7.23
(t, J = 8.0 Hz, 4H), 6.86 (t, J = 7.3 Hz, 2H), 3.35 (dd, J = 27.5, 10.5
Hz, 8H), 0.63 (s, 12H). 11B NMR (128 MHz, CD3CN): δ 21.09 (s).
13C{1H} NMR (100 MHz, C6D6): δ 147.6, 128.9, 121.2, 118.4, 72.6,
Preparation of 3ha. The reaction was performed following the
general procedure. H NMR yield: 90%. The residue was purified by
1
flash column chromatography (silica gel, hexane/ethyl acetate 20:1, v/
1
v) to give the product as a white solid. Yield: 53 mg, 84%. H NMR
(400 MHz, CDCl3): δ 7.60 (br s, 1H), 7.41 (s, 1H), 7.22 (d, J = 8.2
Hz, 1H), 7.10 (dd, J = 8.3, 1.3 Hz, 1H), 4.84 (s, 2H), 2.72 (t, J = 5.7
Hz, 4H), 1.99−1.83 (m, 4H), 0.97 (s, 9H), 0.12 (s, 6H). 13C{1H}
NMR (100 MHz, CDCl3): δ 135.1, 134.5, 132.3, 127.9, 120.3, 115.9,
110.4, 110.2, 66.2, 26.2, 23.4, 23.4, 23.4, 21.0, 18.7, −4.9. GC−MS
(EI) m/z (relative intensity): 315 (M+, 15), 258 (M+ − C(CH3)3,
t
25), 184 (M+ − C(CH3)3 − OSiMe2 Bu, 100). HRMS (FAB) m/z:
[M − H+] calcd for 314.1940; found, 314.1942.
Preparation of 3ia. The reaction was performed following the
1
general procedure. H NMR yield: 23%. The residue was purified by
31.8, 21.5. The NMR data were consistent with the reported data.34
Stoichiometric Reaction of 5 and 2a (Scheme 3B). Inside a
glovebox in an oven-dried J-young NMR tube, N,N′-bis-
[(neopentylglycolatoboryl)-1,2-diphenylhydrazine (5, 0.10 mmol,
41.0 mg), 2a (0.20 mmol, 21 μL), and C6D6 (0.40 mL) were
added. The reaction mixture was heated at 100 °C for 24 h. After the
reaction time, the tube was left for cooling to ambient temperature
flash column chromatography (silica gel, hexane/ethyl acetate 40:1, v/
1
v) to give the product as a white solid. Yield: 7 mg, 19%. H NMR
(400 MHz, CDCl3): δ 7.59 (br s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.01
(t, J = 7.5 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 2.80−2.68 (m, 4H), 2.46
(s, 3H), 1.99−1.80 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ
135.2, 133.9, 127.5, 121.9, 119.5, 119.5, 115.7, 110.9, 23.5, 23.5, 23.4,
21.2, 16.8. The NMR data were consistent with the reported data.32
Preparation of 3cv in 0.2 mmol-scale reaction (two-step one-pot
manner): (step 1) inside a glovebox in an oven-dried J-young NMR
tube, B2nep2 (0.44 mmol, 100 mg), 1,2-bis(p-tolyl)diazene (1c, 0.20
mmol, 42.0 mg), 4,4′-bipyridyl (0.0080 mmol, 1.25 mg), and C6D6
(0.4 mL) were added. The reaction mixture was heated at 100 °C for
5 h. During the first 10 min in order to dissolve all the solids, the tube
was gently placed upside down (once or twice) and put it back at 100
°C bath. (Step 2) After that time, the tube was left for cooling to
ambient temperature and N-methyl-4-piperidone (2v, 0.40 mmol, 50
μL) was added under inert conditions, and the reaction further heated
at 100 °C for 24 h. After that time and after reaching ambient
1
and the internal standard (TMB) was added, the H NMR indicated
the formation of 3aa in 89% yield.
Stoichiometric Reaction of 5 and 2a in the Presence of
B2nep2 (Scheme 3C). Inside a glovebox in an oven-dried J-young
NMR tube, N,N′-bis[(neopentylglycolatoboryl)-1,2-diphenylhydra-
zine (5, 0.10 mmol, 41.0 mg), 2a (0.20 mmol, 21 μL), B2nep2
(0.11 mmol, 25 mg), and C6D6 (0.40 mL) were added. The reaction
mixture was heated at 100 °C for 2 h. After the reaction time, the tube
was left for cooling to ambient temperature, the solvent and volatiles
were removed under vacuum, then CH2Br2 was added as the internal
standard, CDCl3 was also added, and 1H NMR was measured,
3296
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
indicating the formation of 3aa in 70% yield. Without B2nep2, 3aa was
not detected under the same reaction conditions.
Kohei Nishi − Department of Chemistry, Graduate School of
Engineering Science, Osaka University, Toyonaka, Osaka
560-8531, Japan
Observation of Enamine 7 as a Reaction Intermediate
(Scheme 3D). Inside a glovebox in an oven-dried J-young NMR
tube, N,N′-bis[(neopentylglycolatoboryl)-1,2-diphenylhydrazine (5,
0.10 mmol, 41.0 mg), 2a (0.20 mmol, 21 μL), B2nep2 (0.11 mmol, 25
mg), and C6D6 (0.40 mL) were added. The reaction mixture was
heated at 50 °C for 16 h. After that time, the tube was left for cooling
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02661
Notes
1
to ambient temperature and H NMR was measured, indicating the
The authors declare no competing financial interest.
formation of 7 in 54% yield along with 3aa in 10% yield. Then, the
same reaction vessel was heated at 100 °C for 2 h. Then, the tube was
1
left for cooling to ambient temperature and H NMR was measured
ACKNOWLEDGMENTS
■
again, revealing the consumption of 7 with increasing the amount of
1
L.C.M.C. acknowledges the financial support by the JSPS
Research Fellowships (P18336). I.S. acknowledges the scholar-
ship from JICA Innovative Asia Program (D1805473).
3aa in 64% yield. The H NMR spectra of the reaction progress are
shown in Figures S2 and S3 in Supporting Information.
Insertion of Benzaldehyde into N−B Bonds of 5 (eq 3).
Inside a glovebox in an oven-dried J-young NMR tube, N,N′-
bis[(neopentylglycolatoboryl)-1,2-diphenylhydrazine (5, 0.10 mmol,
41.0 mg), benzaldehyde (0.20 mmol, 21 μL), and C6D6 (0.40 mL)
were added. The reaction mixture was heated at 100 °C for 2 h. After
that time, the tube was left for cooling to ambient temperature. The
volatiles were removed under vacuum to give yellow oil of 8, and
REFERENCES
■
(1) (a) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.;
Verma, A.; Choi, E. Biomedical Importance of Indoles. Molecules
2013, 18, 6620−6662. (b) Kim, M. B.; O’Brien, T. E.; Moore, J. T.;
Anderson, D. E.; Foss, M. H.; Weibel, D. B.; Ames, J. B.; Shaw, J. T.
The Synthesis and Antimicrobial Activity of Heterocyclic Derivatives
of Totarol. ACS Med. Chem. Lett. 2012, 3, 818−822. (c) Kochanow-
ska-Karamyan, A. J.; Hamann, M. T. Marine Indole Alkaloids:
Potential New Drug Leads for the Control of Depression and Anxiety.
Chem. Rev. 2010, 110, 4489−4497. (d) Gribble, G. W. Recent
developments in indole ring synthesismethodology and applica-
tions. J. Chem. Soc., Perkin Trans. 1 2000, 1045−1075.
1
C6D6 (0.40 mL) was added for H, 11B, and 13C NMR character-
ization. Because of its instability, HRMS characterization was
1
unsuccessful. H NMR (400 MHz, C6D6): δ 7.60 (d, J = 7.1 Hz,
4H), 7.10−7.00 (m, 14H), 6.80 (t, J = 7.6 Hz, 2H), 6.25 (s, 2H), 3.33
(s; 8H), 0.57 (s, 12H). 11B NMR (128 MHz, CD3CN): δ 17.22 (s).
13C{1H} NMR (100 MHz, C6D6): δ 150.1, 138.9, 129.3, 129.1, 128.7,
127.7, 121.6, 115.3, 94.6, 73.0, 31.5, 21.3.
Synthesis of 3aa from 1,2-Diphenylhydrazine. Inside a
glovebox in an oven-dried J-young NMR tube, 1,2-diphenylhydrazine
(6, 0.20 mmol, 36.8 mg), 2a (0.20 mmol, 21 μL), and C6D6 (0.40
mL) were added. The reaction was heated at 100 °C for 24 h. After
that time, the tube was left for cooling to ambient temperature, and
1H NMR measurement clarified the formation of 3aa in 33% yield. In
the second reaction under similar conditions, bis(neopentylglyco-
lato)diboron (1.1 equiv, 0.22 mmol, 50 mg) was added, and 3aa was
(2) (a) Gribble, G. W. Heterocyclic chemistry is the biggest branch
of chemistry covering two-third of the chemical literature. Heterocyclic
Scaffolds II: Reactions and Applications of Indoles; Springer: Berlin,
2010. (b) Stempel, E.; Gaich, T. Cyclohepta[b]indoles: A Privileged
Structure Motif in Natural Products and Drug Design. Acc. Chem. Res.
2016, 49, 2390−2402. (c) Somei, M.; Yamada, F. Simple indole
alkaloids and those with a non-rearranged monoterpenoid unit. Nat.
Prod. Rep. 2005, 22, 73−103. (d) Kozmin, S. A.; Iwama, T.; Huang,
Y.; Rawal, V. H. An Efficient Approach to Aspidosperma Alkaloids via
[4 + 2] Cycloadditions of Aminosiloxydienes: Stereocontrolled Total
Synthesis of ( )-Tabersonine. Gram-Scale Catalytic Asymmetric
Syntheses of (+)-Tabersonine and (+)-16-Methoxytabersonine.
Asymmetric Syntheses of (+)-Aspidospermidine and (−)-Quebrach-
amine. J. Am. Chem. Soc. 2002, 124, 4628−4641.
1
obtained in 60% yield (by H NMR).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02661.
(3) (a) Bugaenko, D. I.; Karchava, A. V.; Yurovskaya, M. A.
Synthesis of indoles: recent advances. Russ. Chem. Rev. 2019, 88, 99−
159. (b) Inman, M.; Moody, C. J. Indole synthesis something old,
something new. Chem. Sci. 2013, 4, 29−41. (c) Vicente, R. Recent
advances in indole syntheses: New routes for a classic target. Org.
Biomol. Chem. 2011, 9, 6469−6480. (d) Taber, D. F.; Tirunahari, P.
K. Indole synthesis: a review and proposed classification. Tetrahedron
2011, 67, 7195−7210.
1H NMR spectra of the time-course analysis and 1H and
13C{1H} NMR of reaction products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
(4) Humphrey, G. R.; Kuethe, J. T. Practical Methodologies for the
Synthesis of Indoles. Chem. Rev. 2006, 106, 2875−2911.
(5) (a) Fischer, E.; Jourdan, F. Ueber die Hydrazine der
Hayato Tsurugi − Department of Chemistry, Graduate School
of Engineering Science, Osaka University, Toyonaka, Osaka
560-8531, Japan; orcid.org/0000-0003-2942-7705;
Email: tsurugi@chem.es.osaka-u.ac.jp
Kazushi Mashima − Department of Chemistry, Graduate
School of Engineering Science, Osaka University, Toyonaka,
Osaka 560-8531, Japan; orcid.org/0000-0002-1316-
2995; Email: mashima@chem.es.osaka-u.ac.jp
̈
Brenztraubensaure. Ber. Dtsch. Chem. Ges. 1883, 16, 2241−2245.
(b) Fischer, E.; Hess, O. Synthese von Indolderivaten. Ber. Dtsch.
Chem. Ges. 1884, 17, 559−568. (c) Irgashev, R. A.; Steparuk, A. S.;
Rusinov, G. L. A new convenient synthetic route towards 2-
(hetero)aryl-substituted thieno[3,2-b]indoles using Fischer indoliza-
tion. Org. Biomol. Chem. 2018, 16, 4821−4832. (d) Kotha, S.;
Chakkapalli, C. Application of Fischer Indolization under Green
Conditions using Deep Eutectic Solvents. Chem. Rec. 2017, 17, 1039−
1058. (e) Heravi, M. M.; Rohani, S.; Zadsirjan, V.; Zahedi, N. Fischer
indole synthesis applied to the total synthesis of natural products. RSC
Adv. 2017, 7, 52852−52887. (f) Irgashev, R. A.; Karmatsky, A. A.;
Rusinov, G. L.; Charushin, V. N. Construction of Heteroacenes with
Fused Thiophene and Pyrrole Rings via the Fischer Indolization
Reaction. Org. Lett. 2016, 18, 804−807. (g) Inman, M.; Carbone, A.;
Moody, C. J. Two-Step Route to Indoles and Analogues from
Authors
Luis C. Misal Castro − Department of Chemistry, Graduate
School of Engineering Science, Osaka University, Toyonaka,
Osaka 560-8531, Japan
Ibrahim Sultan − Department of Chemistry, Graduate School
of Engineering Science, Osaka University, Toyonaka, Osaka
560-8531, Japan
3297
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Haloarenes: A Variation on the Fischer Indole Synthesis. J. Org. Chem.
2012, 77, 1217−1232.
(6) Sayyed, I. A.; Alex, K.; Tillack, A.; Schwarz, N.; Michalik, D.;
Beller, M. A Convenient and General Method for the Synthesis of
Indole-2,3-dicarboxylates and 2-Arylindole-3-carboxylates. Eur. J. Org.
Chem. 2007, 2007, 4525−4528.
(7) Zhan, F.; Liang, G. Formation of Enehydrazine Intermediates
through Coupling of Phenylhydrazines with Vinyl Halides: Entry into
the Fischer Indole Synthesis. Angew. Chem., Int. Ed. 2013, 52, 1266−
1269.
(16) Yan, Z.; Xie, X.; Song, Q.; Ma, F.; Sui, X.; Huo, Z.; Ma, M.
Tandem selective reduction of nitroarenes catalyzed by palladium
nanoclusters. Green Chem. 2020, 22, 1301−1307.
̈
(17) (a) Gore, S.; Baskaran, S.; Konig, B. Fischer Indole Synthesis in
Low Melting Mixtures. Org. Lett. 2012, 14, 4568−4571. (b) Park, I.-
K.; Suh, S.-E.; Lim, B.-Y.; Cho, C.-G. Aryl Hydrazide beyond as
Surrogate of Aryl Hydrazine in the Fischer Indolization: The
Synthesis of N-Cbz-indoles, N-Cbz-carbazoles, and N,N′-Bis-Cbz-
pyrrolo[2,3-f]indoles. Org. Lett. 2009, 11, 5454−5456.
(18) (a) Oshima, K.; Ohmura, T.; Suginome, M. Dearomatizing
conversion of pyrazines to 1,4-dihydropyrazine derivatives via
transition-metal-free diboration, silaboration, and hydroboration.
Chem. Commun. 2012, 48, 8571−8573. (b) Ohmura, T.; Morimasa,
Y.; Suginome, M. Organocatalytic Diboration Involving “Reductive
Addition” Boron-Boron σ-Bond to 4,4’-Bipyridine. J. Am. Chem. Soc.
2015, 137, 2852−2855. (c) Ohmura, T.; Morimasa, Y.; Suginome, M.
4,4’-Bipyridine-catalyzed Stereoselective trans-Diboration of Acetyle-
nedicarboxylates to 2,3-Diborylfumarates. Chem. Lett. 2017, 46,
1793−1796.
(19) (a) Wang, G.; Zhang, H.; Zhao, J.; Li, W.; Cao, J.; Zhu, C.; Li,
S. Homolytic Cleavage of a B−B Bond by the Cooperative Catalysis
of Two Lewis Bases: Computational Design and Experimental
Verification. Angew. Chem., Int. Ed. 2016, 55, 5985−5989. (b) Beagan,
D. M.; Carta, V.; Caulton, K. G. A reagent for heteroatom borylation,
including iron mediated reductive deoxygenation of nitrate yielding a
dinitrosyl complex. Dalton Trans. 2020, 49, 1681−1687.
(20) Sokolova, N. V.; Nenajdenko, V. G.; Sokolov, V. B.;
Vinogradova, D. V.; Shevtsova, E. F.; Dubova, L. G.; Bachurin, S.
O. Synthesis and biological activity of N-substituted-tetrahydro-γ-
carbolines containing peptide residues. Beilstein J. Org. Chem. 2014,
10, 155−162.
(21) Merino, E. Synthesis of azobenzenes: the coloured pieces of
molecular materials. Chem. Soc. Rev. 2011, 40, 3835−3853.
(22) Song, H.; Yang, Z.; Tung, C.-H.; Wang, W. Iron-Catalyzed
Reductive Coupling of Nitroarenes with Olefins: Intermediate of
Iron−Nitroso Complex. ACS Catal. 2020, 10, 276−281.
(23) Lin, Y.; Ye, J.; Zhang, W.; Gao, Y.; Chen, H. Catalytic Oxidative
Coupling Cyclization for Construction of Benzofuroindolenines under
Mild Reaction Conditions. Adv. Synth. Catal. 2019, 361, 432−435.
(24) Ferguson, F. M.; Fedorov, O.; Chaikuad, A.; Philpott, M.;
Muniz, J. R. C.; Felletar, I.; von Delft, F.; Heightman, T.; Knapp, S.;
Abell, C.; Ciulli, A. Targeting Low-Druggability Bromodomains:
Fragment Based Screening and Inhibitor Design against the BAZ2B
Bromodomain. J. Med. Chem. 2013, 56, 10183−10187.
(25) Sheng, R.; Zhu, J.; Hu, Y. Mild and Efficient Winterfeldt
Oxidation of 1,2,3,4-Tetrahydro-γ-carbolines for the Synthesis of
Dihydropyrrolo[3,2-b]-quinolones and Pyrrolo[3,2-b]quinolones.
Molecules 2012, 17, 1177−1190.
(26) Ye, J.; Lin, Y.; Liu, Q.; Xu, D.; Wu, F.; Liu, B.; Gao, Y.; Chen,
H. Biomimetic Oxidative Coupling Cyclization Enabling Rapid
Construction of Isochromanoindolenines. Org. Lett. 2018, 20,
5457−5460.
(8) Matcha, K.; Antonchick, A. P. Cascade Multicomponent
Synthesis of Indoles, Pyrazoles, and Pyridazinones by Functionaliza-
tion of Alkenes. Angew. Chem., Int. Ed. 2014, 53, 11960−11964.
(9) (a) Haag, B. A.; Zhang, Z.-G.; Li, J.-S.; Knochel, P. Fischer
Indole Synthesis with Organozinc Reagents. Angew. Chem., Int. Ed.
2010, 49, 9513−9516. (b) Zhang, Z.-G.; Haag, B. A.; Li, J.-S.;
Knochel, P. Efficient Preparation of Polyfunctional Indoles via a Zinc
Organometallic Variation of the Fischer Indole Synthesis. Synthesis
2011, 23−29.
(10) Xu, C.; Xie, W.; Xu, J. Metal-free and regiospecific synthesis of
3-arylindoles. Org. Biomol. Chem. 2020, 18, 2661−2671.
(11) (a) Vivekanand, T.; Satpathi, B.; Bankar, S. K.; Ramasastry, S.
S. V. Recent metal-catalysed approaches for the synthesis of
cyclopenta[b]indoles. RSC Adv. 2018, 8, 18576−18588. (b) Zhao,
D.; Shi, Z.; Glorius, F. Indole Synthesis by Rhodium(III)-Catalyzed
Hydrazine-Directed C-H Activation: Redox-Neutral and Traceless by
N-N Bond Cleavage. Angew. Chem., Int. Ed. 2013, 52, 12426−12429.
(c) Platon, M.; Amardeil, R.; Djakovitch, L.; Hierso, J.-C. Progress in
palladium-based catalytic systems for the sustainable synthesis of
annulated heterocycles: a focus on indole backbones. Chem. Soc. Rev.
2012, 41, 3929−3968. (d) Wei, Y.; Deb, I.; Yoshikai, N. Palladium-
Catalyzed Aerobic Oxidative Cyclization of N-Aryl Imines: Indole
Synthesis from Anilines and Ketones. J. Am. Chem. Soc. 2012, 134,
9098−9101. (e) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Copper
catalysis in the construction of indole and benzo[b]furan rings. Org.
Biomol. Chem. 2011, 9, 641−652. (f) Cacchi, S.; Fabrizi, G. Synthesis
and Functionalization of Indoles Through Palladium-catalyzed
Reactions. Chem. Rev. 2005, 105, 2873−2920. (g) Kruger, K.;
̈
Tillack, A.; Beller, M. Catalytic Synthesis of Indoles from Alkynes.
Adv. Synth. Catal. 2008, 350, 2153−2167.
(12) (a) Oh, Y.; Han, S. H.; Mishra, N. K.; De, U.; Lee, J.; Kim, H.
S.; Jung, Y. H.; Kim, I. S. Synthesis and Anticancer Evaluation of 2,3-
Disubstituted Indoles Derived from Azobenzenes and Internal
Olefins. Eur. J. Org. Chem. 2017, 2017, 6265−6273. (b) Cai, S.;
Lin, S.; Yi, X.; Xi, C. Substrate-Controlled Transformation of
Azobenzenes to Indazoles and Indoles via Rh(III)-Catalysis. J. Org.
Chem. 2017, 82, 512−520.
́
(13) (a) Fra, L.; Millan, A.; Souto, J. A.; Muniz, K. Indole Synthesis
̃
Based On A Modified Koser Reagent. Angew. Chem., Int. Ed. 2014, 53,
7349−7353. (b) Yu, W.; Du, Y.; Zhao, K. PIDA-Mediated Oxidative
C−C Bond Formation: Novel Synthesis of Indoles from N-Aryl
Enamines. Org. Lett. 2009, 11, 2417−2420. (c) Du, Y.; Liu, R.; Linn,
G.; Zhao, K. Synthesis of N-Substituted Indole Derivatives via PIFA-
Mediated Intramolecular Cyclization. Org. Lett. 2006, 8, 5919−5922.
. A review for heterocycle synthesis by organocatalysts, see:
(d) Satpathi, B.; Mondal, A.; Ramasastry, S. S. V. Organocatalytic
Strategies for the Synthesis of Cyclopenta-Fused Arenes and
Heteroarenes. Chem.Asian J. 2018, 13, 1642−1653.
(27) Abe, T.; Shimizu, H.; Takada, S.; Tanaka, T.; Yoshikawa, M.;
Yamada, K. Double “Open and Shut” Transformation of γ-Carbolines
Triggered by Ammonium Salts: One-Pot Synthesis of Multi-
heterocyclic Compounds. Org. Lett. 2018, 20, 1589−1592.
(28) Douki, K.; Ono, H.; Taniguchi, T.; Shimokawa, J.; Kitamura,
M.; Fukuyama, T. Enantioselective Total Synthesis of (+)-Hinckden-
tine A via a Catalytic Dearomatization Approach. J. Am. Chem. Soc.
2016, 138, 14578−14581.
(29) Long, H.; Xu, K.; Chen, S.; Lin, J.; Wu, D.; Wu, B.; Tian, X.;
Ackermann, L. Nickel-Catalyzed Intramolecular Direct Arylation of
Imines toward Diverse Indoles. Org. Lett. 2019, 21, 3053−3056.
(30) Chiba, S.; Hattori, G.; Narasaka, K. Rh(II)-catalyzed Isomer-
ization of 2-Aryl-2H-azirines to 2,3-Disubstituted Indoles. Chem. Lett.
2007, 36, 52−53.
(31) Vargas, D. A.; Tinoco, A.; Tyagi, V.; Fasan, R. Myoglobin-
Catalyzed C-H Functionalization of Unprotected Indoles. Angew.
Chem., Int. Ed. 2018, 57, 9911−9915.
(14) Hosoya, H.; Misal Castro, L. C.; Sultan, I.; Nakajima, Y.;
Ohmura, T.; Sato, K.; Tsurugi, H.; Suginome, M.; Mashima, K. 4,4’-
Bipyridyl-Catalyzed Reduction of Nitroarenes by Bis-
(neopentylglycolato)diboron. Org. Lett. 2019, 21, 9812−9817.
(15) (a) Kokatla, H. P.; Thomson, P. F.; Bae, S.; Doddi, V. R.;
Lakshman, M. K. Reduction of Amine N-Oxides by Diboron
Reagents. J. Org. Chem. 2011, 76, 7842−7848. (b) Bae, S.;
Lakshman, M. K. Unusual Deoxygenation and Reactivity Studies
Related to O6-(Benzotriazol-1-yl)inosine Derivatives. J. Org. Chem.
2008, 73, 1311−1319.
3298
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(32) Pena-López, M.; Neumann, H.; Beller, M. Ruthenium-
̃
Catalyzed Synthesis of Indoles from Anilines and Epoxides.
Chem.Eur. J. 2014, 20, 1818−1824.
(33) Kovacikova, L.; Stefek, M. New Route of Benzyne Cyclization
for Synthesis of 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole Deriva-
tives Avoiding Highly Toxic Aryl Hydrazines. J. Heterocycl. Chem.
2014, 51, 1257−1263.
(34) Ansell, M. B.; Kostakis, G. E.; Braunschweig, H.; Navarro, O.;
Spencer, J. Synthesis of Functionalized Hydrazines: Facile Homoge-
neous (N-Heterocyclic Carbene)-Palladium(0)-Catalyzed Diboration
and Silaboration of Azobenzenes. Adv. Synth. Catal. 2016, 358, 3765−
3769.
3299
https://dx.doi.org/10.1021/acs.joc.0c02661
J. Org. Chem. 2021, 86, 3287−3299