TEMPO/CuI synergetic catalyzed oxidative cross-coupling of indoles with benzylamines: Synthesis of bis(indolyl)phenylmethanes

Article abstract of DOI:10.1080/00397911.2018.1459722

TEMPO/CuI was found to be an effective catalyst for the cross-coupling of indoles with benzylic amines affording the corresponding bis(indolyl)phenylmethanes under air atmosphere at room temperature in good to excellent yields. The efficiency, easy workup, simplicity, and chemoselectivity of this protocol provide a green and low-cost procedure for the synthesis of these compounds.

Full text of DOI:10.1080/00397911.2018.1459722

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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TEMPO/CuI synergetic catalyzed oxidative cross-
coupling of indoles with benzylamines: Synthesis
of bis(indolyl)phenylmethanes
Meixiang Liao, Xiaoyun Zhang & Pengfei Yue
To cite this article: Meixiang Liao, Xiaoyun Zhang & Pengfei Yue (2018) TEMPO/CuI
synergetic catalyzed oxidative cross-coupling of indoles with benzylamines: Synthesis
of bis(indolyl)phenylmethanes, Synthetic Communications, 48:13, 1694-1700, DOI:
10.1080/00397911.2018.1459722
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SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 13, 1694–1700
https://doi.org/10.1080/00397911.2018.1459722
TEMPO/CuI synergetic catalyzed oxidative cross-coupling of
indoles with benzylamines: Synthesis of bis(indolyl)
phenylmethanes
Meixiang Liaoa, Xiaoyun Zhangb, and Pengfei Yuec
aSchool of Pharmaceutical Science, Gannan Medical University, Ganzhou, P. R. China; bDepartment of Drug
c
Inspection, Jiujiang Institute for Food and Drug Control, Jiujiang, P. R. China; Traditional Chinese Medicine
Modern Key Laboratory of the Ministry of Education of TCM, Jiangxi University, Nanchang, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 12 February 2018
TEMPO/CuI was found to be an effective catalyst for the cross-
coupling of indoles with benzylic amines affording the corresponding
bis(indolyl)phenylmethanes under air atmosphere at room tempera-
ture in good to excellent yields. The efficiency, easy workup, simplicity,
and chemoselectivity of this protocol provide a green and low-cost
procedure for the synthesis of these compounds.
KEYWORDS
Benzylamine; bis(indolyl)
methane; indole; TEMPO
GRAPHICAL ABSTRACT
Introduction
The bis(indolyl)alkane and their derivatives are present in various natural products
possessing important biological activity,[1] such as antibacterial, antimicrobial, antibiotic,
anticarcinogenic, genotoxicity, and DNA-damaging properties and are known to have
applications in research areas such as pharmaceuticals and materials science.[2] Therefore,
several synthetic methods for the preparation of bis(indolyl)alkane derivatives have been
reported in the literature by reacting indoles with various aldehydes and ketones in the
presence of either a Lewis acid[3] or a protic acid.[4] Metal triflates[5] such as Ln(OTf)3,
Dy(OTf)3, In(OTf)3, LiClO4,[6] HClO4,[7] and molecular iodine[8] have also been used
for the synthesis of bis(indolyl)alkanes. However, these methods suffer from various
drawbacks such as longer reaction times, use of expensive reagents, low yields, involvement
of complicated purification processes Therefore, the development of simple and convenient
CONTACT Meixiang Liao
licynom1@163.com
School of Pharmaceutical Science, Gannan Medical University,
Ganzhou 341000, P. R. China.
Supplemental data (experimental procedures and 1H and 13C NMR data for all compounds) can be accessed on the
publisher’s website.
© 2018 Taylor & Francis

SYNTHETIC COMMUNICATIONS®
1695
procedures for the synthesis of bis(indolyl)alkanes continues to be a challenging endeavor
in synthetic organic chemistry.
The recent demand for highly efficient and environmentally benign syntheses of fine
chemicals and pharmaceuticals has encouraged the development of mild, safe, and highly
chemoselective catalysts. The persistent nitroxide TEMPO (2,2,6,6-tetramethylpiperidine
N-oxyl radical) and derivatives thereof are highly valuable organocatalysts for the conver-
sion of primary and secondary alcohols to the corresponding carbonyl compounds.[9] The
catalytically active species in most of these reactions is not the nitroxide itself, but its
oxidized form, the corresponding N-oxo-ammonium salt. In practice, the oxoammonium
salt is generated in situ by one-electron oxidation using various organic[10] or inorganic
cooxidants.[11] As a result, dioxygen has been investigated as a terminal oxidant in
nitroxide-based oxidation protocols.[12] Herein, we report a highly selective and
efficient catalytic method for the oxidative cross-coupling of benzylic amines with indoles
to synthesize bis(indolyl)phenylmethane derivatives using TEMPO as the oxidant,
Cu(OAc)2 as the catalyst, and molecular oxygen as the terminal oxidant under an
O2 atmosphere at room temperature.
Results and discussion
Our initial efforts were focused on the investigations with the reaction of indole 1a with
benzylic amine 2a to search for the optimal reaction conditions. The results of these studies
are listed in Table 1. In the first attempt, the reaction was catalyzed by TEMPO (10 mol%)
in the presence of CuSO4 (10 mol%) in CH3CN at room temperature for overnight. To our
Table 1. Optimization of the reaction conditionsa.
Entry
TEMPO (mol%)
Metal (mol%)
Solvent
Isolated yield (%)b
1
2
10
10
10
10
10
10
10
10
10
10
5
15
20
–
15
15
15
15
FeCl3 (10)
FeSO4 (10)
CoCl2 (10)
NiCl2 · 6H2O (10)
LaCl3 · 7H2O (10)
CuSO4 (10)
CuO (10)
Cu2O (10)
CuI (10)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
6
9
3
5
4
10
5
5
6
56
43
61
73
Trace
52
86
85
0
77
69
72
60
7
8
9
10
11
12
13
14
15
16
17
18
–
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CHCl3
CuI (10)
DMF
Benzene
CuI (10)
aThe reaction conditions: indole (1.0 mmol) benzylic amine (0.6 mmol), metal catalyst (0.1 mmol) in 1 mL solvent at RT for
overnight.
bIsolated yield based on indole 1a.

1696
M. LIAO ET AL.
delight, the expected product 3a was isolated and obtained in 56% yield (Table 1, entry 6).
Other metals, such as FeCl3, FeSO4, CoCl2, NiCl2 · 6H2O, and LaCl3 · 7H2O, were examined
subsequently (Table 1, entries 1–5), and copper catalyst was demonstrated to be the best
choice. In light of this result, we decided to investigate this reaction with respect to copper
sources, TEMPO loading, and solvent to achieve the optimal procedure. Evaluation of
copper sources showed that CuI was the best choice in the transformation, affording the
desired product 3a in 73% yield (Table 1, entry 9). However, a trace amount of the targeted
product was observed in a control experiment without the addition of metal salts.
We next examined the effect of TEMPO loading on the reaction, good result was
obtained when using 15 mol% TEMPO (Table 1, entry 12), and there was no advantage
to using more than 15 mol% TEMPO (Table 1, entry 13), whereas the yield significantly
decreased when using only 5 mol% TEMPO (Table 1, entry 11). Control experiments
confirmed that, without TEMPO catalyst, the formation of 3a was not observed (Table 1,
entry 14). After examining different solvents including acetonitrile, THF, CHCl3, C6H6,
and DMF, acetonitrile was found to be most efficient, with which the highest yield of
86% was obtained when using 15 mol% TEMPO and 10 mol% CuI at room temperature
for overnight (Table 1, entry 12).
Having established the optimal reaction conditions, we wanted to investigate the scope
of methodology for the various benzylic amines and indoles. The results are compiled in
Table 2. Table 2 shows that various benzylic amines can react with substituted indoles
to give the corresponding bis(indolyl)phenylmethanes 3 in good to excellent yields.
Indoles can be unsubstituted indoles (Table 2, entries 1–9), N-CH3 (Table 2, entries
Table 2. TEMPO/CuI-catalyzed reaction of benzylic amines with indolesa.
Entry
Compound
R1
R2
R3
Yield (%)b
1
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
H
H
H
H
86
89
81
79
90
80
84
78
75
89
86
82
93
90
92
83
78
H
4-F
3
H
H
4-CH3
4-OCH3
4-CF3
4-Ph
4
H
H
5
H
H
6
H
H
7
H
H
3-Cl
8
H
H
3-CH3
3-OCH3
H
9
H
H
10
11
12
13
14
15
16
17
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
3-Cl
H
3-OCH3
3-NO2
4-CN
4-CF3
3-CH3
3-OCH3
H
H
H
2-CH3
2-CH3
H
aThe reaction conditions: indole (1.0 mmol), benzylic amine (0.6 mmol), TEMPO (0.15 mmol), and CuI (0.1 mmol) in 1 mL
CH3CN at RT for overnight.
bIsolated yield based on 1.

SYNTHETIC COMMUNICATIONS®
1697
10–15), and 2-CH3 (Table 2, entries 16 and 17). The results also have shown that substi-
tution in the benzylamine played a major role in governing the reactivity of the substrate.
With electron-donating substituents in the benzylamines, decreased yields of products were
observed (Table 2, entries 3, 4, 6, 8, and 9). For example, the reaction of 3-methoxybenzyl
amine with indole gave corresponding product 3i in 75% yield (Table 2, entry 9). However,
the effect was reversed when the electron-withdrawing group was present in the
benzylamine. Electron-withdrawing groups (e.g., NO2, CN, and CF3) in the benzylamine
favored the reaction with indoles, affording the corresponding bis(indolyl)phenylmethanes
in high yields (Table 2, entries 5 and 13–15). It is noteworthy that the reaction of N-methyl
indole with benzyl amines gave the corresponding bis(indolyl)phenylmethanes in slightly
better yields (Table 2, entries 10–15).
To expand the scope of the protocol, the reaction of 2-methyl thiophene with various
benzylamines was also evaluated. The results are summarized in Table 3. As shown in
Table 3, good yields were obtained in CH3CN at RT for overnight. Benzylamines with
electron-donating substituents and with electron-withdrawing substituents were all well
tolerant of the reaction conditions. Steric effect also had an adverse influence on the
reaction. For instance, 2-bromo benzylamine gave a lower reaction yield of 67% (Table 3,
entry 7).
To evaluate the practicability of our method, the reaction between indole 1a (5.85 g,
50 mmol) and benzyl amine 2a (3.22 g, 30 mmol) has been performed on a large scale in
a single batch, and to our delight, no yield loss was observed with even lower initiator load-
ing (10 mol% TEMPO/8 mol% CuI in 25 mL CH3CN at room temperature, finished in
10 h, 88% isolated yield). That is to say, here we present a practical and scalable synthetic
entry to the bis(indolyl)phenylmethanes.
We further performed several control experiments under the standard conditions to
probe the reaction mechanism. First, the reaction proceeded badly in argon instead of
air (Scheme 1). Further, we attempted to treat 6 with indole (2 equiv.) 1a under the
standard conditions. Pleasingly, 6 and 1a could smoothly be transformed into 3a in 91%
Table 3. TEMPO/CuI-catalyzed reaction of benzylic amines with 2-methyl thiophenea.
Entry
Compound
R
Yield (%)b
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
H
4-CH3
3-Cl
3-CH3
3-OCH3
3-NO2
2-Br
82
77
85
80
73
93
67
5g
aThe reaction conditions: 2-methyl thiophene (1.0 mmol) and benzyl amine (0.6 mmol), TEMPO (0.15 mmol), and CuI
(0.1 mmol) in 1 mL CH3CN at RT for overnight.
bIsolated yield based on 4.

1698
M. LIAO ET AL.
Scheme 1. Control experiments.
Scheme 2. Proposed reaction pathway of TEMPO/CuI-catalyzed benzylamine with indole.
yield, suggesting that 6 might be an intermediate in this reaction and the reaction
mechanism is similar to the iron-catalyzed oxidative coupling of benzylamines and
indoles.[13b]
Based on the above experimental results and previous reports,[8,13] a plausible reaction
pathway for the TEMPO/CuI-catalyzed benzylamine with indole is shown in Scheme 2.
First, benzylamine was oxidized using TEMPO/CuI in air into imine 7, which should be
unstable and was transformed into corresponding imine 6 by reacting with another amine.
Subsequently, 6 is activated by Cu(I), then performed a nucleophilic addition reaction at
C-3 of indole to give mono(indolyl)phenylmethane 8. After the elimination of
BnNHCu(I), the intermediate 9 was generated. Finally, nucleophilic addition of indole
1a to intermediate 9 gave the desired product 3a.[5a,13,14]
Conclusion
In conclusion, we have demonstrated that the TEMPO/CuI is a highly efficient catalyst for
the synthesis of 3,30-bis(indolyl) phenylmethanes from indoles and benzylamines in high
yields. The synthesis proceeds at room temperature without the requirement of inert or
anhydrous reaction conditions. In addition, efficiency, easy workup, simplicity, and
chemoselectivity of this protocol provide a green and low-cost procedure for the synthesis
of these compounds.

SYNTHETIC COMMUNICATIONS®
1699
Experimental section
General procedure for the preparation of bis(indolyl)phenylmethanes 3
To a solution of benzylamine (0.6 mmol), indole (1.0 mmol), and CuI (0.1 mmol) in
CH3CN (1 mL) was added TEMPO (0.15 mmol) under atmosphere and the mixture was
stirred at room temperature for overnight. The reaction mixture was concentrated under
reduced pressure. The residue was purified by flash chromatography on silica gel
(eluant:EtOAc/PE ¼ 1:4) to yield the corresponding product.
Funding
The authors are grateful to the Natural Science Foundation of Jiangxi Province (No:
20161BAB203096) for financial support.
References
[1] (a) Kam, T. S. Alkaloids. In Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Pergamon: Amsterdam, 1999; Vol. 4, pp 429; (b) Irie, T.; Kubushirs, K.; Suzuki, K.; Tsukazaki,
K.; Umezawa, K.; Nozawa, S. Inhibition of Attachment and Chemotactic Invasion of Uterine
Endometrial Cancer Cells by a New Vinca Alkaloid, Conophylline. Anticancer Res. 1999, 19,
3061–3066; (c) Amino, N.; Ohse, T.; Koyano, T.; Umezawa, K. Inhibition of Cellular
Chemotactic Invasion by a Vinca Alkaloid, Conophylline. Anticancer Res. 1996, 16, 55–59;
(d) Umezawa, K.; Ohse, T.; Koyano, T.; Takahashi, Y. Isolation of a New Vinca Alkaloid from
the Leaves of Ervatamia microphylla as an Inhibitor of Ras Functions. Anticancer Res. 1994, 14,
2413–2417; (e) Morris, S. A.; Anderson, R. J. Brominated Bis(indole) Alkaloids from the
Marine Sponge Hexadella sp. Tetrahedron 1990, 46, 715–720; (f) Bifulco, G.; Bruno, I.; Riccio,
R.; Lavayre, J.; Bourdy, G. Further Brominated Bis- and Tris-Indole Alkaloids from the
Deep-Water New Caledonian Marine Sponge Orina sp. J. Nat. Prod. 1995, 58, 1254–1260.
[2] (a) Chakrabarty, M.; Basak, R.; Harigaya, Y. A Sojourn in the Synthesis and Bioactivity of
Diindolylalkanes. Heterocycles 2001, 55, 2431–2447; (b) Benabadji, S. H.; Wen, R.; Zheng, J.;
Dong, X.; Yuan, S. Anticarcinogenic and Antioxidant Activity of Diindolylmethane Derivatives.
Acta Pharmacol. Sin. 2004, 25, 666–671; (c) Hong, C.; Firestone, G. L.; Bjeldanes, L. F. Bcl-2
Family-Mediated Apoptotic Effects of 3,30-Diindolylmethane (DIM) in Human Breast Cancer
Cells. Biochem. Pharmacol. 2002, 63, 1085–1097.
[3] Ji, S.-J.; Zhou, M.-F.; Gu, D.-J.; Jiang, Z.-Q.; Loh, T.-P. Efficient Fe(III)-Catalyzed Synthesis of
Bis(indolyl)methanes in Ionic Liquids. Eur. J. Org. Chem. 2004, 1584, 1587.
[4] (a) Reddy, A. V.; Ravinder, K.; Reddy, V. L. N.; Goud, T. V.; Ravikanth, V.; Venkateswarlu, Y.
Zeolite Catalyzed Synthesis of Bis(indolyl)methanes. Synth. Commun. 2003, 33, 3687–3694;
(b) Mahadevan, A.; Sard, H.; Gonzalez, M.; McKew, J. C. A General Method for C3 Reductive
Alkylation of Indoles. Tetrahedron Lett. 2003, 44, 4589–4591; (c) Roomi, M.; MacDonald, S.
Reductive C-alkylation. Ⅱ. Can. J. Chem. 1970, 48, 139–143; (d) Ramesh, C.; Banerjee, J.;
Pal, R.; Das, B. Silica Supported Sodium Hydrogen Sulfate and Amberlyst-15: Two Efficient
Heterogeneous Catalyst for Facile Synthesis of Bis- and Tris(1H-indol-3-yl)methanes from
Indoles and Carbonyl Compounds. Adv. Synth. Catal. 2003, 345, 557–559.
[5] (a) Chen, D.-P.; Yu, L.-B.; Wang, P.-G. Lewis Acid-Catalyzed Reactions in Protic Media.
Lanthanide-Catalyzed Reactions of Indoles with Aldehydes or Ketones. Tetrahedron Lett. 1996,
37, 4467–4470; (b) Nagarajan, R.; Perumal, P. T. Incl3 and In(OTf)3 Catalyzed Reactions: Synthesis
of 3-Acetyl Indoles, Bis-Indolylmethane and Indolylquinoline Derivatives. Tetrahedron 2002, 58,
1229–1232; (c) Mi, X. L.; Luo, S.-Z.; He, J.-Q.; Cheng, J.-P. Dy(OTf)3 in Ionic Liquid: An Efficient
Catalytic System for Reactions of Indole with Aldehydes/Ketones or Imines. Tetrahedron Lett.
2004, 45, 4567–4570.

1700
M. LIAO ET AL.
[6] Yadav, J. S.; Reddy, B. V. S.; Murthy, C. V. S. R.; Kumar, G. M.; Madan, C. Lithium
Perchlorate Catalyzed Reactions of Indoles: An Expeditious Synthesis of Bis(indolyl) Methanes.
Synthesis-Stuttgart 2001, 5, 783–787.
[7] Nagarajan, R.; Perumal, P. T. Electrophilic Substitution of Indoles Catalyzed by Triphenyl
Phosphonium Perchlorate: Synthesis of 3-Acetyl Indoles and Bis-Indolylmethane Derivatives.
Synth. Commun. 2002, 32, 105–109.
[8] Bandgar, B. P.; Shaikh, K. A. Molecular Iodine-Catalyzed Efficient and Highly Rapid Synthesis
of Bis(indolyl)Methanes Under Mild Conditions. Tetrahedron Lett. 2003, 44, 1959–1961.
[9] For reviews on the application of TEMPO and its derivatives in organic synthesis, see:
(a) Sheldon, R. A.; Arends, I. W. C. E.; Brink, G. J. T.; Dijksman, A. Green, Catalytic Oxidations
of Alcohols. Acc. Chem. Res. 2002, 35, 774–781; (b) Sheldon, R. A.; Arends, I. W. C. E. Orga-
nocatalytic Oxidations Mediated by Nitroxyl Radicals. Adv. Synth. Catal. 2004, 346, 1051–1071;
(c) Bobbitt, J. M.; Bruckner, C.; Merbouh, N. Oxoammonium and Nitroxide-Catalyzed
Oxidations of Alcohols. Org. React. 2009, 74, 103–425; (d) Hu, M.; Song, R. J.; Li, J. H.
Metal-Free Radical 5-exo-Dig Cyclizations of Phenol-Linked 1,6-Enynes for the Synthesis of
Carbonylated Benzofurans. Angew. Chem., Int. Ed. 2015, 54, 608–622; (e) Tebben, L.; Studer,
A. Nitroxides: Applications in Synthesis and in Polymer Chemistry. Angew. Chem. Int. Ed.
2011, 50, 5034–5068; (f) Ciriminna, R.; Pagliaro, M. Industrial Oxidations with Organocatalyst
TEMPO and Its Derivatives. Org. Process Res. & Dev. 2010, 14, 245–251; (g) Garcia-Mancheno,
O.; Stopka, T. TEMPO Derivatives as Alternative Mild Oxidants in Carbon-Carbon
Coupling Reactions. Synthesis 2013, 45, 1602–1611; (h) Zhou, Z.-G.; Liu, L.-X. TEMPO and
Its Derivatives: Synthesis and Applications. Curr. Org. Chem. 2014, 18, 459–474.
[10] (a) Bolm, C.; Magnus, A. S.; Hildebrand, J. P. Catalytic Synthesis of Aldehydes and Ketones
Under Mild Conditions Using TEMPO/Oxone. Org. Lett. 2000, 2, 1173–1175; (b) DeLuca,
L.; Giacomelli, G.; Porcheddu, A. A Very Mild and Chemoselective Oxidation of Alcohols to
Carbonyl Compounds. Org. Lett. 2001, 3, 3041–3043.
[11] (a) Miller, R. A.; Hoerrner, R. S. Iodine as a Chemoselective Reoxidant of TEMPO: Application
to the Oxidation of Alcohols to Aldehydes and Ketones. Org. Lett. 2003, 5, 285–287; (b) Zhao,
M. M.; Li, J.; Mano, E.; Song, Z. J.; Tschaen, D. M. Oxidation of Primary Alcohols to Carboxylic
Acids with Sodium Chlorite Catalyzed by TEMPO and Bleach: 4-Methoxyphenylacetic Acid.
Org. Synth. 2005, 81, 195–203.
[12] For reviews on aerobic oxidations, see: (a) Piera, J.; Bäckvall, J.-E. Catalytic Oxidation of
Organic Substrates by Molecular Oxygen and Hydrogen Peroxide by Multistep Electron Trans-
fer – A Biomimetic Approach. Angew. Chem., Int. Ed. 2008, 47, 3506–3523; (b) Schultz, M. J.;
Sigman, M. S. Recent Advances in Homogeneous Transition Metal-Catalyzed Aerobic Alcohol
Oxidations. Tetrahedron 2006, 62, 8227–8241.
[13] (a) Ji, S.-J.; Wang, S.-Y.; Zhang, Y.; Loh, T.-P. Facile Synthesis of Bis(indolyl)methanes
Using Catalytic Amount of Iodine at Room Temperature Under Solvent-Free Conditions.
Tetrahedron 2004, 60, 2051–2055; (b) Gopalaiah, K.; Chandrudu, S. N.; Devi, A. Iron-Catalyzed
Oxidative Coupling of Benzylamines and Indoles: Novel Approach for Synthesis of Bis(indolyl)
methanes. Synthesis 2015, 47, 1766–1774.
[14] Li, J.; Zhou, M.; Li, B.-G.; Zhang, G.-L. Synthesis of Triindolylmethanes Catalyzed by Zeolites.
Synth. Commun. 2004, 34, 275–280.