Photo-Induced N-N Coupling of o-Nitrobenzyl Alcohols and Indolines to Give N-Aryl-1-amino Indoles

Article abstract of DOI:10.1021/acs.orglett.1c02227

A novel method to synthesize N-aryl-1-amino indoles was established by the photoinduced N-N coupling reaction. This protocol is by treatment of o-nitrobenzyl alcohols and indolines in the presence of TEAI and acetic acid with a 24 W ultraviolet (UV) light

Full text of DOI:10.1021/acs.orglett.1c02227

pubs.acs.org/OrgLett
Letter
Photo-Induced N−N Coupling of o‑Nitrobenzyl Alcohols and
Indolines To Give N‑Aryl-1-amino Indoles
Yifeng Ou, Tianbao Yang, Niu Tang, Shuang-Feng Yin, Nobuaki Kambe, and Renhua Qiu*
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ABSTRACT: A novel method to synthesize N-aryl-1-amino indoles was established by the photoinduced N−N coupling reaction.
This protocol is by treatment of o-nitrobenzyl alcohols and indolines in the presence of TEAI and acetic acid with a 24 W ultraviolet
(UV) light-emitting diode (LED) (385−405 nm) irradiation. The products bearing an aldehyde group can be further transformed to
fluorescent probes based on Rhodamine 6G derivative 11, which shows a high specificity and sensitivity for Fe3+.
Scheme 1. Intermolecular N−N Coupling to Synthesize N-
aryl-1-amino Indoles
ndole derivatives are important bioactive substances that
Iexist widely in many bioactive molecules, drugs, agricultural
chemicals.1 In addition, their application as fluorescent probes
has also been widely reported.2 N-substituted-1-amino indoles
as one of the typical indoles are known for their excellent
activities against the symptoms of Alzheimer’s disease, Chagas
disease, and depression (Figure 1),3 but there is no report on
fluorescent probes.
Figure 1. Representative bioactive N-substituted-1-amino indoles.
Although the synthesis of N-alky and N-heterocycle indoles
has been well-established in organic synthesis,4 the synthesis of
N-amino indoles is still remaining a challenge issue. It can be due
to the high electronegativity of nitrogen5 and cumbersome
procedures. Three pioneering groups have tried two methods to
construct N-aryl-1-amino indoles (Scheme 1). The first protocol
is starting from indole, which can generate 1-amino indole with
hydroxylamine-O-sulfonic acid and strong bases, and followed
by a Pd-catalyzed C−N cross-coupling reaction with relative
halide (Scheme 1a).6 Tunge et al.7 developed another efficient
route using inexpensive Brønsted acid catalysts to promote a
redox amination process, which could efficiently realize the
Received: July 3, 2021
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© XXXX American Chemical Society
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multistep coupling of anilines and indolines to synthesize N-aryl-
1-amino indoles (Scheme 1b).8 Inspiring by these ideas and our
previous finding about o-nitrobenzyl alcohols,9 herein, we
disclosed a protocol which realize the construction of N-aryl-
1-amino indoles in one-pot by a redox coupling process
(Scheme 1c). The inexpensive o-nitrobenzyl alcohols could
produce the oxidized intermediates via a photoinduced method,
which can construct N−N bonds with indolines. These products
bearing an aldehyde or ketone group, can be further transformed
into useful functional molecules, such as fluorescent probes.
We initiated our studies with o-nitrobenzyl alcohol 1a and
indoline 2a as model substrates to screen the reaction conditions
(Table 1). At the outset, we obtained 30% yield with no
promote the process, achieved in 66% yield (Table 1, entries
11−13). The amount of solvent was increased and the self-
coupling products of o-nitrobenzyl alcohol reduced obviously
(Table 1, entry 14). After screening the acids, the combination
of acetic acid and TEAI could greatly improve the reaction yield
to 81% (Table 1, entries 15 and 16). In the end, we screened the
equiv of acetic acid and TEAI, isolated in 86% yield when the
acetic acid and TEAI achieved at 1 equiv (Table 1, entries 17−
19). By the way, we also conducted this reaction under N2
atmosphere and achieved 88% yield.
With the optimized reaction conditions in hand, we
investigated the substrate scope of o-nitrobenzyl alcohols 1
with 2a (Scheme 2). The o-nitrobenzyl alcohol starting materials
(A−J) were prepared by the reductive coupling of o-nitro-
benzaldehyde and phenylboronic acid (see more details in the
Supporting Information). At the outset, we investigated the
effect of methyl groups at different sites on the reaction. The 5-
methyl (3b) delivered the highest yield (87%), oppositely, the 2-
methyl (3c) and 3-methyl (3d) delivered the unsatisfactory
yield (39% and 59%, respectively) because of the steric demands
of reactive intermediate. In the same 5-position, electron-
withdrawing groups (3e−3f) also achieved nice yields in 81%
and 77%, and electron-donating groups (3g) achieved moderate
yield in 58%. Subsequently, the groups with different steric
hindrances at the 4-position (3h−3l) were investigated and
achieved moderate to good yields (59%−72%). In addition, the
absolute configuration of 3e was unambiguously confirmed by
the single-crystal X-ray diffraction.
Next, we further studied the effect of the substituent at the
benzylic position (R) on the reaction. Product 3m with alkyl
group achieved in 62% yield, and the effect that different sites
and various groups on the benzene ring (R) contributes to the
reaction was explored (3n-3r). The m-substituted and p-
substituted substrates had a better reaction effect than the o-
substituted, and both electron withdrawing and electron-
donating groups showed good yields (61%−77%). Products
3s-3t with aryl and heterocycle groups also achieved in 72% and
60%, respectively. We explored the combined effects of the two
substitution sites (3u−3v). They afforded good yields, and the
strong electron-withdrawing group (p-NO2) had a poorer yield
(61%). Finally, the o-nitropyridine alcohols could also be
compatible with the reaction and obtained the 3w in 70% yield.
Ultimately, the generality of the indoline framework was also
examined (Scheme 3). Products 4a−4p with various groups
were achieved in moderate to good yields (37%−85%). The
reaction was compatible with indolines that bearing electron-
withdrawing or electron-donating groups, but the 5-I (4g)
achieved an unsatisfactory yield, because of the dehalogenation.
The strong electron-withdrawing groups, such as 5-CN (4l) and
5-NO2 (4m) afforded the desired products in 61% and 41%,
respectively. Notably, compared with 5-Cl (4e) and 6-Cl (4o)
products, the 7-Cl (4p) had a poorer yield, which could be
explained as a steric effect. Finally, the heterocyclic indoline was
explored, and the product 4q was obtained in good yield (64%).
With the completion of the substrate expansion, we began to
excavate the potential of this skeleton and performed some
functionalized applications. We used p-toluenesulfonyl hydra-
zide 5 to react with 3a to obtain 6 in excellent yield (91%), which
can be used as an intermediate to participate in various
cyclization reactions (Scheme 4a).10 On the other hand, we used
2-bromobenzyl bromide 7 to react with 3a under strong alkaline
conditions to obtain 8. Then, the palladium catalyst, ligand, and
strong base were utilized as partners in an intramolecular
a
Table 1. Optimization of Reaction Conditions
base/acid
(equiv)
solvent
(mL)
entry 1a:2a additive (equiv)
yield (%)
b
1
2
3
4
5
1:1
1:1
1:1
1:1
1:1
−
−
−
−
−
−
MeCN (2.0)
30
32
42
trace
trace
b
b
b
b
K2HPO3 (2.0) MeCN (2.0)
K2HPO3 (2.0) DCM (2.0)
K2HPO3 (2.0) DMF (2.0)
K2HPO3 (2.0) toluene
(2.0)
b
b
c
6
7
8
1:1
3:1
3:1
3:1
3:1
−
−
−
−
−
HCOOK (2.0) DCM (2.0)
38
51
12
n.r.
56
61
−
−
−
−
−
DCM (2.0)
DCM (2.0)
DCM (2.0)
DCM (2.0)
DCM (2.0)
d
9
10
11
3:1 PhI(OAc)2
(0.5)
12
13
14
15
16
17
18
19
20
3:1 TBHP (0.5)
3:1 TEAI (0.5)
3:1 TEAI (0.5)
3:1 TEAI (0.5)
3:1 TEAI (0.5)
2:1 TEAI (0.5)
2:1 TEAI (1.0)
2:1 TEAI (2.0)
2:1 TEAI (1.0)
−
−
−
DCM (2.0)
DCM (2.0)
DCM (4.0)
52
63
68
74
81
79
PhCO2H (0.5) DCM (4.0)
AcOH (0.5)
AcOH (0.5)
AcOH (1.0)
AcOH (2.0)
AcOH (1.0)
DCM (4.0)
DCM (4.0)
DCM (4.0)
DCM (4.0)
DCM (4.0)
e
86 (93)
77
f
88
a
Reaction conditions: 1a (0.4 mmol) 2a (0.2 mmol, 1.0 equiv), TEAI
(0.2 mmol), AcOH (0.2 mmol), solvent (4.0 mL), 24 h, room
temperature, with a 24 W UV LEDs (385−405 nm) irradiation under
b
c
air. Isolated yields. With UV light (350−380 nm) irradiation. With
d
e
blue light (440−460 nm) irradiation. No light. Yields determined
f
by GC-MS. N2.
additives (Table 1, entry 1), and the weak base K2HPO3 might
promote the reaction (Table 1, entry 2). Then the solvents and
bases were screened, the bases helped little, and the DCM was
the superior solvent (Table 1, entries 3−6). We adjusted the
ratio to 3:1 (1a:2a) because of the ordinary conversion of 1a,
and the yield reached 51% yield simultaneously (Table 1, entry
7). Subsequently, the light source was screened, and the UV light
(385−405 nm) achieved the highest yield in 56%. Meanwhile,
the reaction did not start with no light irradiation (Table 1,
entries 8−10). Some additives were added and oxidants did not
seem to work, but the tetraethylammonium iodide (TEAI)
could better reduce the production of byproduct indole to
B
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a
a
Scheme 2. Substrate Scope of o-Nitrobenzyl Alcohols
Scheme 3. Substrate Scope of Indolines
a
Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol, 1.0 equiv), TEAI
(0.2 mmol), AcOH (0.2 mmol), DCM (4.0 mL), 24 h, room
temperature, with a 24 W UV LEDs (385−405 nm) irradiation under
air. Isolated yields.
Scheme 4. Synthetic Applications
a
Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol, 1.0 equiv), TEAI
(0.2 mmol), AcOH (0.2 mmol), DCM (4.0 mL), 24 h, room
temperature, with a 24 W UV LEDs (385−405 nm) irradiation under
air. Isolated yields.
cyclization method to synthesize 9 whose analogues had nice
antiproliferative activity (Scheme 4b).6a,11 A cyclic derivative of
Rhodamine 6G 10 could react with 3a to form an imine
compound 11, which may be used for detecting metal ions
(Scheme 4c).12 By the way, the aldehyde group could be
removed by palladium catalysts, and obtained the desired
product 12 in 57% yield.13
In order to verify the advantages of 11 as a fluorescent probe,
we used common metal cations to explore its sensitivity and
specificity for Fe3+. As shown in Figure 2, the color changes
(Figure 2A) were from colorless to pink and fluorescence
changes (Figure 2B) were from colorless to yellow. Variations of
UV−vis (Figure 2C) and fluorescence spectra (Figure 2D) of 11
(20 μM) caused by Fe3+ and other mixed metal cations were
recorded in Figure 2. Obviously, after adding Fe3+, the solution
which only contained 11 or contained 11 and other mixed-metal
cations (including Fe2+, K+, Mg2+, Cu2+, Hg2+, Na+, Ni2+, Pb2+,
Zn2+, and Ag+, 50 μM, respectively) both had strong absorption
at 527 nm and strong emission at 555 nm. Compared with other
fluorescent probes which could respond to both Fe3+ and
Hg2+,14 our fluorescent probe 11 could specifically recognize
Fe3+ in complicated environments, which can be explained as the
coordination of Fe3+ and N-aryl-1-amino indole formed a large
C
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Scheme 5. Gram-Scale Synthesis and Mechanistic Studies
Figure 2. (A) Color changes (X = Fe2+, K+, Mg2+, Cu2+, Hg2+, Na+, Ni2+,
Pb2+, Zn2+, and Ag+); (B) fluorescence changes; (C) UV-vis spectra of
11 (X and Fe3+ are 50 μM, respectively); (D) fluorescence spectra of
11. (E) UV-vis spectra of 11 (Fe3+ concentrations of 0, 10, 20, 30, 40, 50
μM); (F) fluorescence spectra of 11 (Fe3+ concentrations of 0, 2.5, 5,
10, 20, 30, 40, 50 μM). See Figures S6 and S7 in the Supporting
Information) for the full-size panels.
under the standard conditions, obtained 3a in 65% and 52%
when alkoxyl groups were methyl and benzyl, respectively
(Scheme 5b (2)). It revealed that there may be some oxygen
transfer and alkoxy group departure routes in these processes.
Two equivalents of radical scavengers were added to the reaction
to investigate whether there were other types of free radicals in
the system (Scheme 5b (3)). We did not detect any other
trapped radicals via GC-MS, which revealed that the reaction
route is redox coupling of nitrosobenzene intermediates and
indolines. We used intermolecular benzyl alcohol and nitro-
benzene compounds to conduct with indoline under standard
conditions (Scheme 5b (4)), and no reaction was observed. This
experiment revealed that the intramolecular o-nitrobenzyl
alcohol was necessary for the reaction. We also used some
other secondary amines such as N-ethylaniline, 1,2,3,4-
tetrahydro quinoline and tetrahydro pyrrole, etc. to react with
1a under the standard conditions, but no desired products were
detected (Figure S4 in the Supporting Information). Then we
conducted a light on−off experiment, which revealed that light
was indispensable to promote the reaction (Figure S5(a) in the
Supporting Information). In order to verify the promotion effect
of TEAI, we conducted a monitoring control experiment under
standard conditions, and found that TEAI could inhibit the
production of byproduct indole (see Figure S5(b) in the
Supporting Information).
steric hindrance structure (for changes of chemical shifts in 1H
NMR chart, see Figure S8 in the Supporting Information). A
spectral variation of 11 upon the gradual addition of Fe3+ (0−2.5
equiv) was shown in Figure 2 with a standard solution.
Obviously, the absorption spectra (Figure 2E) and emission
bands (Figure 2F) were gradually enhanced with an increasing
concentration of Fe3+ ions. Based on the above experimental
results, we have proven that 11 had high selectivity and
sensitivity for Fe3+ ions as a novel fluorescent probe.
To show the practicability of this protocol, we used a high-
power argon lamp as the light source to conduct a gram-scale
reaction (Scheme 5a). The nitrogen environment was used to
prevent the rapid oxidation of indoline at high concentrations.
After stirring for 4 days, the product 3a (1.06 g) was obtained
with 75% yield. To gain mechanistic insights into these
processes, the following control experiments were conducted.
At first, nitrosobenzene 13 could react with indoline in the
presence of TEAI and acetic acid, which afforded the desired
product 12 in 86% yield (Scheme 5b (1)). On the basis of redox
amination, we hypothesized that the indoline and nitro-
sobenzene 13 combined into an azo ion intermediate, then
experienced a series of proton transfer to construct 12. This
experiment demonstrated that nitrosobenzene derivative were
the key intermediates. Next, we conducted 14 with indoline
D
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Based on the above experiments and previous literature
reports,7,15 we have proposed a plausible reaction mechanism.
At first, o-nitrobenzyl alcohol 1a transforms to intermediate 17
under the irradiation of UV light quickly. The intermediate 17
can transform to its conjugate base 17− spontaneously under
alkaline conditions. By the ring fragmentation, intermediate 18
transforms to transient hemiketal species 19, then loses 1 equiv
of water to afford o-nitrosobenzaldehyde 20. Because of the high
activity of 20 and the reducibility of indoline,7 they combine
with each other to generate intermediate 21. In this process, we
used TEAI to inhibit the production of byproduct indole.
Then,15d the azo ion 21 may experience a deprotonation process
to form azomethine ylide 22, which could transform to a new
iminium ion 23, because of the reprotonation of the dipolar
intermediate. Finally, the π-bond hyperconjugation effect and
proton loss lead to the aromatization and formation of 3a.
In conclusion, we have developed a new method for the
synthesis of N-aryl-1-amino indoles by UV light-induced
reductive amination coupling reaction. As active intermediates
of the redox coupling process, nitrosobenzene species could
react with reductive indolines, which were facilitated by mild
Brønsted acid and TEAI catalysts. Based on the molecular
skeleton, we have developed a new Rhodamine-based
fluorescent probe, which showed “turn-on” fluorescent and
real-time colorimetric responses to Fe3+ in a mixed-metal-
cations environment with high selectivity and sensitivity.
Tianbao Yang − State Key Laboratory of Chemo/Biosensing
and Chemometrics, Advanced Catalytic Engineering Research
Center of the Ministry of Education, College of Chemistry and
Chemical Engineering, Hunan University, Changsha 410082,
People’s Republic of China
Niu Tang − State Key Laboratory of Chemo/Biosensing and
Chemometrics, Advanced Catalytic Engineering Research
Center of the Ministry of Education, College of Chemistry and
Chemical Engineering, Hunan University, Changsha 410082,
People’s Republic of China
Shuang-Feng Yin − State Key Laboratory of Chemo/Biosensing
and Chemometrics, Advanced Catalytic Engineering Research
Center of the Ministry of Education, College of Chemistry and
Chemical Engineering, Hunan University, Changsha 410082,
People’s Republic of China
Nobuaki Kambe − State Key Laboratory of Chemo/Biosensing
and Chemometrics, Advanced Catalytic Engineering Research
Center of the Ministry of Education, College of Chemistry and
Chemical Engineering, Hunan University, Changsha 410082,
People’s Republic of China; The Institute of Scientific and
Industrial Research, Osaka University, Ibaraki, Osaka 567-
0047, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02227
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02227.
■
sı
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (Nos. 21878071 and 21971060), the Natural Science
Foundation of Changsha (No. kq2004008), Hu-Xiang High
Talent of Hunan Province (No. 2018RS3042), and the
Recruitment Program for Foreign Experts of China (No.
WQ20164300353) for financial support.
Detailed experimental procedures, characterization data,
spectra data of the 1H, 13C, and 19F NMR for raw materials
and obtained products (PDF)
HRMS data (ZIP)
FAIR data, including the primary NMR FID files, for
compounds 3a−w, 4a−q, A-J, 6, 8, 9, 11, 12 (ZIP)
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CCDC 2088706 contains the supplementary crystallographic
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AUTHOR INFORMATION
Corresponding Author
■
Renhua Qiu − State Key Laboratory of Chemo/Biosensing and
Chemometrics, Advanced Catalytic Engineering Research
Center of the Ministry of Education, College of Chemistry and
Chemical Engineering, Hunan University, Changsha 410082,
People’s Republic of China; orcid.org/0000-0002-8423-
9988; Email: renhuaqiu1@hnu.edu.cn
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Yifeng Ou − State Key Laboratory of Chemo/Biosensing and
Chemometrics, Advanced Catalytic Engineering Research
Center of the Ministry of Education, College of Chemistry and
Chemical Engineering, Hunan University, Changsha 410082,
People’s Republic of China
E
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