Acid-catalyzed three-component addition of carbonyl compounds with 1,2,3-triazoles and indoles

Article abstract of DOI:10.1039/d1ob01451j

A facile and efficient acid-catalyzed three-component reaction of indoles, 1-tosyl-1,2,3-triazoles and carbonyl compounds has been developed. The use of TsOH with a small amount of water significantly promoted the reaction yield. This method provided a general and one-pot approach for the synthesis of structurally diverseC3-alkylated indole derivatives. The alkylation exclusively occurred at theN²position of triazoles. Various functional groups were tolerated under the optimized simple reaction conditions.

Full text of DOI:10.1039/d1ob01451j

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Q. Xing, C. Zhou,
S. Jiang, S. Chen and G. Deng, Org. Biomol. Chem., 2021, DOI: 10.1039/D1OB01451J.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Page 1 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D1OB01451J
Journal name
Research Article
Acid-Catalyzed Three-Component Addition of Carbonyl
Compounds with 1,2,3-Triazoles and Indoles
Qiaoyan Xing, Chunlan Zhou, Shuxin Jiang, Shanping Chen and Guo-Jun Deng*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
R
R
O
N
N
A facile and efficient acid-catalyzed three-component reaction of
indoles, 1-tosyl-1,2,3-triazoles and carbonyl compounds has been
developed. The use of TsOH with a small amount of water
significantly promoted the reaction yield. This method provided
a general and one-pot approach to structurally diverse C3-
alkylated indole derivatives. The alkylation position exclusively
occured at the N2 position of triazoles. Various functional groups
were tolerated under the optimized simple reaction conditions.
N
N
N
N
N
N
OMe
N
N
new OLED reagent
anxiolytics
O
O
Organic compounds containing multiple nitrogen atoms have
always been a hot spot pursued by organic chemists due to their
outstanding application value in many fields such as material
science,1 biological research,2 and medicinal chemistry.3 Among
them, compounds containing indole skeleton have undergone
continuous research for decades.4 On the other hand, N2-alkylated
triazoles exhibit a broad spectrum of biological activities,5 such as
anti-bacterial, anti-microbial, anti-tumor, antidepressant and so on.
The combination of these two important nitrogen-containing
molecules can provide more opportunities for further study of their
bioactivities.
Me
H
O
N
R
O
N
N
N
HO
N
N
O
O
N
F
targeting agents for cancer
antimicrobial activity
especially N2-heterocyclic products, have remarkable application
value in both
Scheme 1 Examples of biologically active N2-alkylated tria
zoles.
The rise of “click reactions” has made triazole compounds an
important source for C-N bond construction. 1-Tosyl-4-aryl/alkyl-
1,2,3-triazole was unstable because of the electron-withdrawing
nature of the tosyl group. The triazole ring tends to open and form N-
tosyl-α-diazo imine because of the weak N1−N2 bond.6 Due to the
unstable property of the triazole, most of the research mainly
focused on the triazole ring opening transformation to provide a
nitrogen atom, thus the atomic economy of the reaction is reduced.
In recent years, considerable researches have been focused on
keeping the triazole moiety in the product. Various reactions were
realized involved the triazole functional group such as alkylation,7
alkenyla tion,8 and heterocyclization reactions at the N1 position.9
However, selectivity control is always a problematic issue along
with this kind of reaction. Furthermore, the N2 substituted products,
Key Laboratory for Green Organic Synthesis and Application of Hunan Province，
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry
of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
E-mail: gjdeng@xtu.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 5
COMMUNICATION
Journal Name
To further improve the reaction yield, variousViewacAirdtiscle Ownelinree
investigated for this kind of transformationDbOaIs:e1d0.1o0n39o/uDr1OpBre0v14io5u1Js
research. The addition of 10 mol% of HCl (6 mol/L) slightly
improved the reaction yield to 28% (entry 2), indicating that acidic
environment was effective. To our delight, the desired product 4a
was obtained in 54% yield when catalytic amounts of TfOH was
added, showing that organic acid may more effective (entry 5).
TsOH with a crystal water exhibited a gratifying yield of 60% (entry
6). To find the exact role of water in this kind of reaction, 2.5 eq. of
H2O was added to the reaction mixture and we were glad to find that
the reaction yield could be further improved to 72% (entry 14). The
reaction solvent is important to the reaction and lower yield was
observed when the reaction was carried out under toluene (entry 7).
Other non-polar solvents such as cyclohexane were not as effective
as polar solvents. Better yields were achieved when the reaction was
carried out in polar solvents such as DCM, PhCl and o-
dichlorobenzene (entries 8-10). However, no product was found in
DMSO (entry 9). Good yield was still achieved when the reaction
was carried at 50 oC or 70 oC (entries 11-12). Extending the reaction
time to 28 hours can slightly increase the yield to 76% (entry 14).
However, further extension of the reaction time will decrease the
yield (see SI). Meanwhile, substrate ratio investigation indicated that
a slight excess of cyclohexanone substrate was essential and the
yield was decreased when the amount of 2a reduced (entry 15).
N2-cyclic progress:
O
Ph
N
a) Mesl(OAc)2
N
OH
N
+
N
b) 20 mol% CuTC,
30 mol% BPhen, BTMG
blue LED, dioxane, r.t., 1h
a)
N
N
Ts
Ph
R1
Ph
N
R2
O
O
N
N
Radical Reaction
O
O
N
b)
c)
N
R2
+
N
R1
80 o
C
Ph
N
Sc(OTf)3
N
+
N
N
N
H
N
O
this work:
CHO
Ph
N
N3
N3
N2
N1
R
N1
N2
d)
Ph
N1
N2
N3
Ts
H
65 o
C
60 o
C
N
R
N
Ph
Ph
R
9 examples
yield up to 68%
metal-free & high selectivity
chiral or latent centers
24 examples
yield up to 86%
Scheme 2 Synthesis of N2-alkylated triazoles
biomedicine and organic optoelectronic materials (Scheme 1).
However, efficient related synthesis methods are rare and mostly of
them are limited to two-component reactions. In 2018, David
MacMillan and co-workers used cyclohexanecarboxylic acids and
triazole compounds as the substrates to generate N2 cyclohexyl
products via decarboxylative coupling process under copper and
photo-catalysed conditions (Scheme 2).10 Subsequently, Xia and co-
workers designed a free radical reaction pathway to realize the
coupling of triazole and furan to obtain N2 heterocyclic products, yet
the products are limited to the five-membered ring.11 Later in 2020,
Tang first used cyclohexanone as the raw material for C-N bond
synthesis to selectively give N2 cyclohexyl products using treated
triazoles.12 These methods were proved to be versatile for the
functionalization of 1,2,3-triazoles while maintaining the triazole
motif in the product structure, general, efficient and multi-
component synthetic methods for the preparation triazole derivatives
are still desirable.13 In recent years, our group have developed
various methods for bis-functionalization of cyclohexanone’s
carbonyl group and its ortho carbon under transition-metal free
conditions.14 We envision that it might be possible to use
cyclohexanone to connect the two important indole and triazole
motifs in one-pot. Surprisingly, our preliminary studies revealed that
the two functional molecules were not attached to the carbonyl group
and its ortho site as expected, but to both carbonyl carbon (Scheme
2d). This special result encourages us to further optimized the
reaction conditions systematically. Herein, we reported a simple and
efficient method for the synthesis of indole derivatives via
assembling of carbonyl compounds with indoles and triazoles under
metal-free conditions.
Table 1. Optimization of Reaction Conditionsa
O
Ph
N
N
Ph
catalyst
temp.
N
N
+
+
N
N
N
N
Ts
1a
2a
3a
4a
Entry Acid
1
Solvent
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
Toluene 60
DCM
DMSO
PhCl
o-DCB
o-DCB
o-DCB
o-DCB
o-DCB
Temp.(oC) Yield (%)b
60
60
60
60
60
60
17
33
28
28
54
60
45
55
0
2
HCl
3
4
5
H3PO4
AcOH
TfOH
6
7
8
9
10
11
12
13c
14c,d
15c,e
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
60
60
60
50
70
60
60
60
58
48
57
72
76
53
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), 3a (0.2 mmol),
o
b
acid (10 mol%), solvent (1 ml), 60 C for 24 h under air. Isolated
yield. c H2O (2.5 eq.). d For 28 h. e 2a (0.2 mmol).
To obtain optimization conditions for the three-component
With the optimized conditions in hand, we first investigated
reaction, 1-methyl-1H-indole (1a), cyclohexanone (2a), and 4- the substrate scope of indole derivatives and the results were
phenyl-1-tosyl-1H-1,2,3-triazole (3a) were initially used as the summarized in Table 2. Various indoles bearing electron-
standard substrates (Table 1). The desired product 4a could be withdrawing and electron-donating substituents at the indole
obtained in low yield even without any additional additives when the benzene ring could be used to generate the expected products in
o
reaction was carried out at 60 C in 1,2-dichlorobenzene (entry 1). moderate to excellent yields. Functional groups such as methyl,
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 5
Organic & Biomolecular Chemistry
Journal Name
COMMUNICATION
methoxy and OBn were all well tolerated under the given Table 3 Substrate scope with respect to 4-phenyl-1-tosyl-
View Article Online
reaction conditions (4b-4d). Notably, reactive halogen 1H-1,2,3-triazole derivativesa
DOI: 10.1039/D1OB01451J
substituents such as fluoro, chloro and bromo could even
slightly improve the reaction yields (4e-4g), allowing to access
R
R
O
H2O (2.5 eq.)
TsOH• H2O (10 mol %)
N
more complex molecules through next coupling of these
halogen-substituted products. The substituent position in the
benzene ring of indole substrates did not significantly affect the
reaction yield and good yields could be obtained when the
substituents were located at C6 (4h-4j). Moderate yield still
could be achieved when a methyl group presented at the C7
position(4k). In addition, better yield was obtained when N-
methyl indole was replaced by N-ethyl indole (4l).
N
N
+
+
N
N
N
N
60 oC, 28 h
N
Ts
1a
2
3
4
O
4m
4q
R = 4-F, , 65%
R = 4-CH3,
R = 4-CH2CH3, , 54%
4o
, 62%
4n
4r
R = 4-Cl, , 84%
4s
R = 4-Br, , 71%
R = 4-OCH3, , 46%
4p
4t
R = 3-CH3, , 60%
2a
R = 4-OCH2CH3, , 55%
Ph
N
4u
R = 3-F,
R
, 62%
O
H2O (2.5 eq.)
TsOH• H2O (10 mol %)
N
Ph
Br
Ph
CHO
N
N
H2O (2.5 eq.)
Br
TsOH• H2O (10 mol%)
N
N
Ph
Br
H
N
N
N
R
+
+
N
60 oC, 28 h
+
N
+
N
N
N
N
toluene, 65 o
C
Ts
3a
Et
R
N
Ts
N
1
2a
N
4
N
N
N
N
Ph
Ph
N
Ph
N
Et
N
N
1
2
3a
N
N
N
N
N
5
N
N
N
N
N
N
O
w
4
, 33%
x
4
, 20%
4v
2059165
)
, 55% (
N
N
N
Ph
Ph
Ph
N
N
H
H
N
H
N
4a
4c
N
, 72%
, 76%
4b
, 47%
N
N
N
Ph
Ph
Ph
N
N
N
N
N
N
N
N
N
N
N
N
N
BnO
F
Cl
Et
Et
Et
5a
5b
5c
, 30%
, 68%
, 57%
N
N
N
F
Cl
Br
4d
, 82%
4e
4f
, 72%
, 86%
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
H
H
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Br
N
N
N
N
N
N
F
Et
Et
Et
4g
4h
4i
, 83%
, 78%
, 66%
5d
5e
5f
, 47%
, 48%
, 52%
Ph
Ph
Ph
Cl
N
Cl
N
N
N
N
Ph
N
Cl
Ph
N
Ph
N
N
N
N
H
N
H
N
N
N
N
N
N
N
N
N
Cl
N
N
N
4j
4k
4l
, 81%
, 72%
, 60%
Et
Et
Et
5g
5h
5i
, trace
, 53%
, 55%
Table 2 Substrate scope with N-methyl indolea
a
a Conditions: 1 (0.2 mmol), 2a (0.4 mmol), 3a (0.2 mmol), acid
Conditions: 1a (0.2 mmol), 2 (0.4 mmol), 3 (0.2 mmol), acid
(10 mol%), H2O (2.5 eq.), solvent (1 ml), 60 C for 28 h under (10 mol%), H2O (2.5 eq.), solvent (1 ml), 60 C for 28 h under
o
o
air.
air.
Table 4 Substrate scope with respect to benzaldehydea
a
1 (0.2 mmol), 2 (0.4 mmol), 3a (0.2 mmol), catalyst (10 mol%),
H2O (2.5 eq.) and solvent (1 ml) at 65 oC for 28 h under air.
Subsequently, we shift the focus of the reaction on 4-phenyl-
1-tosyl-1H-1,2,3-triazole derivates with cyclic ketones and N-
methyl indole to explore whether the difference of the
substituents will affect the chemical selectivity of the product
(Table 3). When the substituents are electron donating groups
such as methyl, ethyl, methoxy and ethoxy, the reaction could
be smoothly proceeded to give the desired products in moderate
yields (4m-4p). When the electron-withdrawing substituent on
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 5
COMMUNICATION
Journal Name
Scheme 3 Control Experiments
the benzene ring such as fluoro, chloro and bromo were existed,
the reaction results were even better, delivering the N2-cyclohexyl
products in good yields (4q-4s). The electronic effect of the meta
substituent did not show significant effect on the reaction yield and
selectivity (4t-4u). The structure of 4v was further confirmed by
single-crystal X-ray diffraction. Other cyclic ketones, such as cyclo
pentanone and cycloheptanone were investigated under similar reac
tion conditions and lower reaction yields were achieved (4w and 4x).
View Article Online
DOI: 10.1039/D1OB01451J
In order to explore the mechanism of the reaction, we carried
out a series of control experiments (Scheme 3). When the
reaction time was shortened to 12 hours, we found that in
addition to the target product 4a (38% isolated yield), there was
a condensation by-product 6 (20% yield detected by GC) which
was generated by addition reaction of two molecules of indole
with cyclohexanone (Scheme 3a). In the absence 3a, 6-8 were
observed by GC-MS analysis and based on the basis of our
previous studies (Scheme 3b).14b Equivalent compound 6
reacted with 3a to give the desired product 4a in low yield
(Scheme 3c). However, treatment of possible intermediates 7
and 8 could not give the product 4a under the standard reaction
conditions (Scheme 3d). Interestingly, when 4-phenyl-1H-
1,2,3-triazole (3a') was used instead of 3a for this reaction, no
desired product 4a could be obtained (Scheme 3e). This
reaction indicated that the Ts group was not removed in the first
step.
Furthermore, other carbonyl compounds such as aromatic
aldehydes were also able to apply for this kind addition after
some fine- tuning of the conditions (Table 4). Aromatic
aldehydes with various substituents could smoothly react with
indole derivatives and 4- phenyl-1-tosyl-1H-1,2,3-triazole (3a)
to form a chemically selective product 5 with a chiral center.
When benzaldehyde was used, the corresponding product 5a was
obtained in 68% yield. Electron-donating alkyl substituents such as
methyl and tert-butyl both gave lower yields of N2-selective products
(5b and 5c). Electron-withdrawing substituents such as fluoro,
chloro and bromo were all able to be tolerated under the given
reaction conditions, leading to moderate yields of the desired
products (5d-5f). However, benzaldehydes with strong electron-
withdrawing groups such as nitro and trifluoromethyl, only gave
trace amount of the desired product and a large amount of raw
materials were left. The position of the substituent did not affect the
result of the reaction obviously (5g and 5h). When aromatic ketones
such as acetophenone were treated under the optimized reaction
conditions, we found that the reaction activity of acetophenone was
Based on the control experimental results and previous related
literature,14 we proposed a possible reaction mechanism for this kind
of transformation (Scheme 4). Initially, addition of indole with
cyclohexanone under acidic conditions form the corresponding
intermediate B. On the same time, 4-phenyl-1-tosyl-1H-1,2,3-
triazole (3a) proceeds a classic autocatalysis process in the presence
of p-toluene sulfonic acid providing a nitrogen anion D after a series
of electron transfer.15 The combination of B and D generates the
desired product 4a. Meanwhile, carbocation B can also undergo
nucleophilic addition with another molecule of indole to form 6.
O
Ph
N
standard conditions
6
N
a)
+
+
4a
+
N
N
N
12 h
Ts
1a
N
H
O
1a
2a
3a
OH
H+
GC
38%
6
TsOH
, 20%
+
N
N
H2O
N
O
2a
1a
B
A
standard conditions
28 h
b)
c)
+
+
+
6
N
N
N
Ph
N
N
Ph
H+
Ph
TsOH
H2O
N
N
27%GC
18%
12%
GC
GC
1a
2a
7,
8,
N
N
N-
N
N-
-Ts
Ts
N
Ph
Ph
N
D
N
standard conditions
3a
C
+
N
N
N
28 h
N
4a
N
N
Ts
Scheme 4 Possible reaction mechanism
.
3a
6
4a,
23%
In summary, we developed a gentle and efficient method for the
addition of carbonyl compounds with indoles and 1,2,3-triazoles in
the absence of metal-catalyst. The reaction selectivity could be well
controlled under this simple and mild reaction conditions. Two
important functional molecules were selectively added to the same
carbonyl carbon site. When aromatic aldehydes were used for this
kind of reaction, a chiral center was generated which provided more
opportunities for further functionalization.
d)
N
Ph
N
standard conditions
28 h
+
+
3a
N
N
N
N
N
4a,
0%
7
8
O
Ph
N
N
Ph
N
+
standard conditions
28 h
e)
+
N
N
N
H
N
1a
2a
3a'
4a,
0%
Acknowledgements
very low and only a small amount of reaction product was detected
This work was supported by the National Natural Science
Foundation of China (21871226, 21572194), the Innovative
(5i).
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 5 of 5
Organic & Biomolecular Chemistry
Journal Name
COMMUNICATION
Erkelens, J. R. Mellema and P. C. Fernandes, JV. ieOwrAgrt.icClehOenmlin.e,
1984, 49, 2197.
Foundation for Postgraduate Scientific Research Fund of Xiangtan
University (XDCX2020B118) and the Undergraduate Investigated
Study and Innovated Experiment Plan from Ministry of Education of
China and Hunan Province.
DOI: 10.1039/D1OB01451J
7
8
9
(a) K. Huang, G. R. Sheng, P. Lu and Y. G. Wang, J. Org.
Chem., 2017, 82, 5294; (b) S. Kunikazu, H. Nobuko and K.
Kiyosi, Chem. Soc. Jpn., 1986, 59, 179; (c) S. Pati, R. G.
Almeida, E. N. Silva and I. N. N. Namboothiri, Beilstein J. Org.
Chem., 2021, 17, 762.
(a) H. J. J. Loozen and E. F. Godefroi, J. Org. Chem., 1973, 38,
1056; (b) H. F. Duan, W. M. Yan, S. Sengupta and X. D. Shi,
Med. Chem. Lett., 2009, 19, 3899; (c) M. Kavitha, B. Mahipal,
P. S. Mainkar and S. Chandrasekhar, Tetrahedron Lett., 2011,
52, 1658.
Notes and references
1
(a) T. Gadzikwa, O. K. Farha, C. D. Malliakas, M. G.
Kanatzidis, J. T. Hupp and S. B. T. Nguyen, J. Am. Chem. Soc.,
2009, 131, 13613; (b) P. L. Golasa and K. Matyjaszewski, Chem.
Soc. Rev., 2010, 39, 1338; (c) H. M. Li, F. Y. Cheng, A. M. Duft
and A. Adronov, J. Am. Chem. Soc., 2005, 127, 14518; (d) M.
Wyszogrodzka and R. Haag, Chem. Eur. J., 2008, 14, 9202; (e)
D. I. Rozkiewicz, D. Janczewski, W. Verboom, B. J. Ravoo and
D. N. Reinhoudt, Angew. Chem. Int. Ed., 2006, 45, 5292.
(a) A. M. Phil, P. Schmieder, R. Kühne and J. Rademann,
Angew. Chem. Int. Ed., 2009, 48, 5042; (b) M. E. Hahn and T.
W. Muir, TRENDS in Biochemical Sciences., 2005, 30, 26; (c)
W. P. Heal, S. R. Wickramasinghe, R. J. Leatherbarrow and E.
W. Tate, Org. Biomol. Chem., 2008, 6, 2308; (d) G. Schneider,
Nature Reviews Drug Discovery., 2010, 9, 273; (e) M. F.
Schmidt, A. I. Llobet, M. Lisurek, A. E. Dahshan, J. Z. Tan, R.
Hilgenfeld and J. Rademann, Angew. Chem. Int. Ed., 2008, 47,
3275; (f) A. Kornberg, TRENDS in Biochemical Sciences., 2003,
28, 515; (g) G. Klebe, Drug Discov. Today. 2006, 11, 580; (h) H.
Mauser and W. Guba, Curr. Opin. Drug Discov. Devel., 2008,
11, 365.
M. B. Harisha, M. Nagaraj, S. Muthusubramanian and N.
Bhuvanesh, RSC Adv., 2016, 6, 58118.
10 Y. F. Liang, X. H. Zhang and D. W. C. MacMillan, Nature.,
2018, 559, 83.
11 Z. Li, Q. H. Wei, L. L. Song, W. Y. J. Han, X. Wu, Y. Zhao, F.
Xia and S. Y. Liu, Org. Lett., 2019, 21, 6413.
12 S. B. Tang, J. L. Yu, Y. Shao and J. Sun, Org. Chem. Front.,
2021, 8, 278.
2
13. For selected reviews on multi-component reaction, see: (a) C. M.
Volla, I. Atodiresei and M. Rueping, Chem. Rev., 2014, 114,
2390; (b) L. Levi and T. J. J. Müller, Chem. Soc. Rev., 2016, 45,
2825. For some recent selected examples, see: (c) Y. Wu, J. Y.
Chen, J. Ning, X. Jiang, J. Deng, Y. Deng, R. Xu and W. M. He,
Green Chem., 2021, 23, 3950; (d) N. Meng, Y. F. Lv, Q. S. Liu,
R. S. Liu, X. H. Zhao and W. Wei, Chin. Chem. Lett., 2021, 32,
258; (e) Q. W. Gui, F. Teng, S. N. Ying, Y. Liu, T. Guo, J. X.
Tang, J. Y. Chen, Z. Cao and W. M. He, Chin. Chem. Lett.,
2020, 31, 3241.
14 (a) S. P. Chen, Y. X. Li, P. H. Ni, H. W. Huang and G. J. Deng,
Org. Lett., 2016, 18, 5384; (b) S. P. Chen, Y. F. Liao, F. Zhao, H.
R. Qi, S. W. Liu and G. J. Deng, Org. Lett., 2014, 16, 1618; (c) S.
P. Chen, L. R. Wang, J. Zhang, Z. R. Hao, H. W. Huang and G. J.
Deng, J. Org. Chem., 2017, 82, 11182.
3
(a) Y. M. Chabre and R. Roy, Current Topics in Medicinal
Chemistry., 2008, 8, 1237; (b) M. ColomboI and l. Peretto,
Drug. Discov. Today., 2008, 13, 677; (c) R. Hanselmann, G. E.
Job, G. Johnson, R. L. Lou and J. G. Martynow, Org. Process
Res. Dev., 2010, 14, 152; (d) R. Moumné, V. Larue, B. Seijo, T.
Lecourt, L. Micouin and C. Tisné, Org. Biomol. Chem., 2010, 8,
1154; (e) A. S. Kiselyov, M. Semenova and V. V. Semenov,
Bioorg. Med. Chem. Lett., 2009, 19, 1344; (f) B. Japelj, S.
Recnik, P. Cebasek, B. Stanovnik and J. Svete, J. Heterocycl.
Chem., 2005, 42, 1167.
4
For some recent examples of natural products containing the
indole moiety, see (a) N. Y. Ji, X. M. Li, L. P. Ding and B. G.
Wang, Helv. Chim. Acta., 2007, 90, 385; (b) S. R. Walker, E. J.
Carter, B. C. Huff and J. C. Morris, Chem. Rev., 2009, 109,
3080; (c) R. J. Melander, M. J. Minvielle and C. Melander,
Tetrahedron., 2014, 70, 6363; (d) S. M. Allina, C. I. Thomasa, J.
E. Allarda, K. D. Mark and R. J. Elsegooda, Tetrahedron Lett.,
2004, 45, 7103; (e) M. B. Johansen and M. A. Kerr, Org. Lett.,
2008, 10, 3497; (f) S. Rajasekar, D. Yadagiri and P. Anbarasan,
Chem. Eur. J., 2015, 21, 17079; (g) M. Berger, J. A. Gray and B.
L. Roth, Annu. Rev. Med., 2009, 60, 355; (h) R. Faust, P. J.
Garratt, R. Jones and L. K. Yeh, J. Med. Chem., 2000, 43, 1050.
For selected examples of N2-alkylation, see: (a) J. Das, C. V. L.
Rao, T. V. R. S. Sastry, M. Roshaiah, P. G. Sankar, A. Khadeer,
M. S. Kumar, A. Mallik, N. Selvakumar, J. Iqbal and S. Trehan,
Med. Chem. Lett., 2005, 15, 337; (b) M. Bretner, A. Baier, K.
Kopańska, A. Najda, A. Schoof, M. Reinholz, A. Lipniacki, A.
Piasek, T. Kulikowski and P. Borowski, Antiviral Chem.
Chemother., 2005, 16, 315; (c) M. H. Paluchowska, R. Bugno, S.
C. Minol, A. J. Bojarski, E. Tatarczyńska and E. C. Wójcik,
Arch. Pharm. Chem. Life Sci., 2006, 339, 498; (d) P. P. Dixit, V.
J. Patil, P. S. Nair, S. Jain, N. Sinha and S. K. Arora, Eur. J.
Med. Chem., 2006, 41, 423; (e) Z. Rezaei, S. Khabnadideh, K.
Pakshir, Z. Hossaini, F. Amiri and E. Assadpour, Eur. J. Med.
Chem., 2009, 44, 3064.
15 H. H. Dong, D. D. Zhang, R. J. Fang, Q. Y. Du, Z. Y. Dong, H.
Wei, M. Shi and F. J. Wang, Synthetic Communications., 2018,
10, 1227.
5
6
(a) M. E. Hermes and F. D. Marsh, J. Am. Chem. Soc., 1967, 89,
4760; (b) R. E. Harmon, F. J. Stanley, S. K. Gupta and J. N.
Johnson, J. Org. Chem., 1970, 35, 3444; (c) C. L. Habraken, C.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins