Cobalt-Catalyzed C?H Nitration of Indoles by Employing a Removable Directing Group

Article abstract of DOI:10.1002/asia.201800036

A mild and efficient C(sp²)?H nitration of 3-substituted indoles, by using the economical and non-toxic cobalt nitrate hexahydrate [Co(NO₃)₂?6 H₂O] as a catalyst and tert-butyl nitrite (TBN) as the nitro source, is reported. This approach provides a unique methodology involving a site-selective C?N bond formation for preparation of C-2 substituted nitro indoles. Utilization of the tBoc as the removable directing group enhances the synthetic utility of the method.

Full text of DOI:10.1002/asia.201800036

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Cobalt-Catalyzed C-H Nitration of Indoles Employing a
Removable Directing Group
Authors: Paridhi Saxena and Manmohan Kapur
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Asian J. 10.1002/asia.201800036
Link to VoR: http://dx.doi.org/10.1002/asia.201800036
A Journal of
A sister journal of Angewandte Chemie
and Chemistry – A European Journal

10.1002/asia.201800036
Chemistry - An Asian Journal
FULL PAPER
Cobalt-Catalyzed C-H Nitration of Indoles Employing a
Removable Directing Group
Paridhi Saxena and Manmohan Kapur*
Abstract: A mild and efficient C(sp2)-H nitration of 3-substituted
indoles, using the economical and non-toxic cobalt nitrate
hexahydrate [Co(NO3)2.6H2O] as catalyst and tert-butyl nitrite (TBN)
as the nitro source, is being reported. This approach provides a
unique methodology involving a site-selective C-N bond formation
for preparation of C-2 substituted nitro indoles. Utilization of the tBoc
as the removable directing group enhances the synthetic utility of the
method.
developed a regioselective nickel-catalyzed remote C-H nitration
of 2-aryloxazoline amides using tert-butyl nitrite as a nitro
source.10f To the best of our knowledge, the transition metal-
catalyzed C-2 nitration of indoles has not yet been explored and
still remains
a great challenge as it suffers from poor
regioselectivity. Therefore, development of an efficient catalytic
approach for the C(sp2)-H nitration of indoles is greatly desired.
In this context we report herein, a cobalt-catalyzed C(sp2)-H
nitration of 3-substituted indoles under mild reaction conditions
and involving the use of tert-butyl carboxylate (tBoc) as a
removable directing group (Scheme 1).
Introduction
The transition metal catalyzed functionalization of C-H bonds is
a unique synthetic strategy for regioselective C-C or C-X bond
construction.1 A variety of directing groups have been utilized for
the directed C-H functionalization which has been recognized as
a straightforward and efficient method for enabling quick access
to an array of structurally diversified molecules. Nitrogen
heterocycles such as indoles are biologically interesting
scaffolds owing to their prevalence in bioactive natural
products.2 Introduction of an amine functional group at the C-2
position of indoles is a challenging task. One method of
introducing the amino group is via nitration and subsequent
functionalization.3 The traditional nitration methods possess
limitations such as poor functional group compatibility, use of
harsh reaction conditions and possible overnitration.4 Thus, to
overcome these issues, several approaches have been
developed for regioselective nitration.5,6 Over the past few years
significant progress in C(sp2)-H nitration using ortho-metallation
strategy has been achieved. Majority of the reports
predominantly employ complexes of Pd, Rh and Cu as
catalysts.7 Our group recently reported a palladium-catalyzed,
heteroatom-directed strategy for ortho-nitration of anilines
employing a removable pyrimidine directing group.7l Recently,
Ribas8a and co-workers described the first example of a cobalt-
catalyzed remote C-H functionalization of 8-aminoquinoline
based on a single electron transfer (SET) mechanism. Das and
co-workers demonstrated a cobalt-catalyzed, proton-coupled
electron transfer (PCET) mediated regioselective ortho-specific
nitration of aromatic C(sp2)-H bonds using 2-aminopyridine as
directing group.8c
Scheme 1. Cobalt-catalyzed C(sp2)-H nitration of indoles
Results and Discussion
We commenced our investigations by screening several
catalysts with a various nitro sources and solvents. With a
variety of directing groups at the nitrogen, the reaction resulted
mostly in complex mixtures when the C-3 position was
unsubstituted. We then proceeded with N-Boc-3-methyl indole
as a model substrate to screen the reaction conditions (Table 1,
see supporting information for complete optimization). Our initial
efforts were directed towards Pd-catalysis but in this case the
reaction failed to give desired product and minor amount of
indolon-2-one was obtained (Entry 3, Table 1).11 The cobalt
catalyst to be initially screened was Co(NO3)2.6H2O in the
presence of t-BuNO2 as the nitro source and K2S2O8 as a
oxidant in TFE at room temperature (Entry 9, Table 1). The
corresponding product was obtained with 51% yield. The
reaction showed inferior results with other cobalt catalyst such
as CoBr2, Co(OAc)2, Co(acac)2 and we also found that
Co(NO3)2.6H2O in absence of the nitro source does not lead to
desired product. Several other nitro sources were examined and
we observed that t-BuNO2 gave the best results. In an attempt to
improve the yield, many oxidants (eg. Oxone, PIFA), were
screened and K2S2O8 was found to give the best yield. Next, the
effect of solvent was also investigated. We found that reaction
proceeded in TFE with moderate yield with a considerably
shorter reaction time. Unlike in TFE, the reaction was
comparatively slower in THF but resulted in better yield and a
cleaner conversion. The reaction showed low efficiency when
molecular oxygen was not used. On increasing the catalyst
loading to beyond 40 mol%, the product yield was dramatically
reduced.
In recent times, considerable interest has been shown towards
first-row transition metal catalysts as they are cost-efficient and
naturally more abundant.9,10 Guo and co-workers recently
[a]
Paridhi Saxena and Dr. Manmohan Kapur
Department of Chemistry
Indian Institute of Science Education and Research Bhopal
Academic Building II, Bhopal Bypass Road, Bhauri,
Bhopal 462066, MP, India.
E-mail: mk@iiserb.ac.in
Supporting information for this article is given via a link at the end of
the document.
The best condition was found to be Co(NO3)2.6H2O (10 mol%)/
t-BuNO2 (2.0 equiv)/ K2S2O8 (2.0 equiv)/ O2 (balloon) in THF at
room temperature (Entry 11, Table 1). We next investigated
several other directing groups7h to check their compatibility with
the nitration protocol. However, under the optimized reaction
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800036
Chemistry - An Asian Journal
FULL PAPER
conditions, only traces of the expected product was obtained in
case of the 2-pyridyl group whereas no product formation was
observed with 2-pyrimidyl as a directing group. When acetyl was
employed as the directing group, the expected product was not
obtained.
To explore the reaction pathway, control experiments were
carried out. The experiment with 1.0 equiv of the metal catalyst
did not result in any conversion to product, indicative that the
nitrate from the catalyst was not acting as the nitro source
(Scheme 4A). It is noteworthy to report when nitration reaction
was performed using Pd-catalysis it did not give the
corresponding product 2a and instead several side products
were formed. Interestingly, the Pd-catalysis when attempted with
2.0 equiv AgNO2 yielded 3-acetoxy indolin-2-ones (3a, Scheme
4B) in 34% yield.11
Table 1. Optimization Studies[a]
Entry
Conditions
HNO3 /AcOH
Pd(OAc)2/ AgNO2/ K2S2O8/ DCE
Pd(OAc)2/ AgNO2/ K2S2O8/ AcOH/DCE
Yield (%)b of 2a
1
2
3
<5c
NR
4
5
6
7
Pd(OAc)2/ t-BuNO2/ K2S2O8/ DCE
[Ru(p-cym)Cl2]2/ AgNO2/ K2S2O8/ AgSbF6/ DCE
CuCl2.2H2O/ Fe(NO3)3.9H2O/ DCE
Cu(OAc)2/ t-BuNO2/ K2S2O8/ TFE
Fe(NO3)3.9H2O/ DCE
10c
<5c
Complex mixture
NRc
8
NR
9
Co(NO3)2.6H2O/ t-BuNO2/ K2S2O8/ O2/ TFE
Co(NO3)2.6H2O/ AgNO2/ K2S2O8/ O2/ TFE
Co(NO3)2.6H2O/ t-BuNO2/ K2S2O8/ O2/ THF
Co(NO3)2.6H2O/ K2S2O8/ O2/ THF
Co(NO3)2.6H2O/ t-BuNO2/ O2/ TFE
CoBr2/ t-BuNO2/ K2S2O8/ O2/ TFE
Co(OAc)2/ t-BuNO2/ K2S2O8/ O2/ TFE
Co(acac)2/ t-BuNO2/ K2S2O8/ O2/ TFE
Mn(OAc)2/ t-BuNO2/ K2S2O8/ O2/ TFE
Sc(OTf)2/ t-BuNO2/ K2S2O8/ O2/ TFE
51
26
71
NR
10
11
12
13
14
15
16
17
18
12
Complex mixture
42c
<5c
NR
10c
[a]Reaction conditions: Unless otherwise mentioned, all the reactions
performed with 1a (0.15 mmol), catalyst (10 mol%), nitro source (2.0 equiv),
oxidant (2.0 equiv) and additive (2.0 equiv) in 1 mL of solvent. [b]Isolated yield.
[c]Complex mixture was obtained. NR
= No Reaction. Boc = tert-butyl
carboxylate, DCE = 1,2-dichloroethane, TFE = 2,2,2 trifluoroethanol.
With the optimized reaction conditions established, we explored
the scope and generality of this Co-catalyzed C-2 nitration of 3-
substituted indoles. A wide range of 3-substituted N-Boc indoles
reacted smoothly resulting in the corresponding product in
moderate to good yield (Scheme 2). The reaction worked well
with substituents at the C-5, C-6 as well as C-7 positions (2a-2k,
Scheme 2),11 with a few exceptions (2e, 2f, Scheme 2). The
results also showed that the reaction had excellent
regioselectivity and compatibility with alkyl, methoxy, halo and
other functional groups. However some electron withdrawing
groups (-NO2, -CN, -COR, -CHO) were not tolerated at C-3. The
benzyl group on 3-position of the indole (2l-2o, Scheme 2) also
showed good regioselectivity to nitration protocol. In addition, a
wide range of long alkyl chain substituted indoles performed well
and furnished the corresponding products (2p-2y, Scheme 2).
The reaction was scalable to gram scale (Compound 2a,
Scheme 2). Surprisingly, tryptamine derived substrate when
subjected to the reaction conditions did not give the desired
product (2z, Scheme 2). Acyl functional groups as well as phenyl
group at C3 were also not tolerated and no transformation was
observed in those cases (See Scheme S1 of Supporting
Information for details).
[a] All yields are isolated yields. [b] carried out on 1 g scale.
Scheme 2. Substrate Scope[a]
Scheme 3. Removal of the Directing Group
To rule out the possibility of electrophilic metalation, we
performed the optimized nitration reaction on N-methyl indole
(Scheme 4C). The substrate did not result in the nitration
product under standard conditions. Subsequently we tried the
reaction with N-methyl-3-methyl indole 5a, which afforded 1,3-
To emphasize the synthetic potential of this methodology, we
attempted the deprotection using TFA in DCM. The reaction
resulted in the corresponding 2-nitroindole derivatives in fairly
good yields (Scheme 3).
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800036
Chemistry - An Asian Journal
FULL PAPER
dimethyl indolin-2-one 5a’ as the only product with 46%
conversion. We also performed control experiments to check
possibility of electrophilic reaction with Lewis acid Sc(OTf)2.13
This reaction condition afforded 2l’ with 15% conversion and
less than 5% C-2 product (2l) was isolated. Next, we performed
competition reactions with electron rich arenes (Scheme 4D),
this exclusively give 2a as the only product and no nitration was
observed on the electron-rich arenes. Similarly no nitration was
observed when electron-rich arenes were subjected to standard
condition. These experimental evidences clearly exclude the
possibility of electrophilic substitution being involved in this
nitration reaction.
involve a radical process. However, considerable reduction in
the yield was observed when 3 equivalents of the spin trap
agent 1,1-diphenyl ethylene was used. In this case, we were
also able to isolate the adduct nitro-diphenyl ethylene (see the
Supporting Information), clearly indicating that a nitro radical
was involved in the reaction.
Scheme 5. Mechanistic Studies
In order to examine the reversibility of the C-H activation step,
we performed the reactions with isotopically labelled solvents
(D2O, MeOH-d4, AcOH-d4) (Scheme 5B). In case of D2O and
MeOH-d4, no deuterium incorporation was observed at the C-2
position of the recovered starting material in either of the case.
Similar results were observed with AcOH-d4 when no nitro
reagent present. These experiments rule out the possibility of C-
H metalation being the reversible step in the nitration reaction.
Surprisingly, with the nitro-source, in case of AcOH-d4, instead
of deuterium incorporation in the starting material, the C-2
nitration product (31%) along with C-6 nitration product (16%)
was observed (see the Supporting Information). This indicated
that in protic media, there was a possibility of generation of the
NO2 cation which led to the electrophilic nitration product at C6
in this case. To further analyze the mechanism of this C(sp2)-H
nitration, the kinetic isotope effect was also determined. The KIE
measured by competitive nitration between 1:1 mixture of 1a
Scheme 4. Control Experiments
1
and 1a-[D1] such that H NMR analysis of the starting material
To obtain mechanistic insights into this Co-catalyzed C-H
nitration, a series of experiments were carried out (Scheme 5).14
To check the possibility of single electron transfer pathway,
showed kH/kD value of 1.0 whereas a value of 0.98 was obtained
for parallel experiments. This suggested that the cleavage of C-
H bond was not involved in the rate-determining step. This also
seemed to indicate that the C-H bond cleavage may not be via a
concerted-metallation-deprotonation (CMD) pathway.
radical trapping experiments were undertaken. Initially
1
equivalent of TEMPO was used as a radical scavenger, which
gave 67% of 2a (Scheme 5A). The radical trap did not inhibit the
reaction which initially led us to believe that the pathway may not
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800036
Chemistry - An Asian Journal
FULL PAPER
dichloroethane were distilled from CaH2. Petroleum ether with a boiling
A plausible mechanism can be proposed on the basis of the
previous reports.8,12 We can propose three possible pathways,
as depicted in Scheme 6. In path A, the Co(II) catalyst is
oxidized to give Co(III) species which reacts with 1a via directed,
range of 40–60 °C was used. Melting points are uncorrected. 1H, and 13
C
NMR: Recorded on Bruker Avance III 400 MHz NMR Spectrometer,
Bruker Avance III 500 MHz NMR Spectrometer; spectra were recorded at
295 K in CDCl3; chemical shifts are calibrated to the residual proton and
carbon resonance of the solvent: CDCl3 (1H δ 7.25; 13C δ 77.0). HRMS:
Bruker Daltonics MicroTOF-Q-II with electron spray ionization (ESI) or
Atmospheric pressure chemical ionization (APCI). GC-HRMS: Performed
on Agilent 7200 GC-QToF (with Electron Impact (EI), 70eV) with 7890A
GC using DB-5 column. GC-LRMS: Performed on Agilent 7890A GC with
Agilent 5975C MS (EI 70 eV) using DB-5 column. IR: Perkin Elmer
Spectrum BX FTIR, Shimadzu IR Affinity-1 FTIR and were recorded as
thin films between KBr plates.
chelation-assisted C-H activation.
The cyclometalated
intermediate 1b undergoes nitro-coordination to generate Co(IV)
intermediate 1c which upon reductive elimination, leads to the
desired nitration product. Path B involves generation of Co(II)
intermediate 1d followed by nitro-coordination to form the
cobaltacycle 1e. Subsequent reductive elimination affords the
desired product and re-oxidation in the presence of oxidant
regenerates the Co(II) species. It may also be possible that the
Co(II) catalyst, upon reaction with NO2 radical is converted to
Co(III) species (Path C, Scheme 6), followed by formation of 1e.
Path C may be the most likely pathway for this transformation,
since it involves a Co(III)-Co(I) pathway which is most widely
The substituted 3-methyl-1H-indoles and 3-benzyl-1H-indoles were
prepared according to procedures reported in literature.[15],[20],[21]
Similarly substituted- 2-(1H-indol-3-yl)acetate and 3-vinylindoles were
also prepared according to literature procedures.[22],[23] 3-vinylindoles
were further reduced according to procedures reported in literature for
preparation of corresponding indoles.
accepted
catalytic
cycle
for
Cobalt-catalyzed
C-H
functionalizations.
General procedure for Boc protection of the synthesised
indoles:[15],[16],[17]
To a solution of the indole (1.70 mmol) in dry CH2Cl2 (4 mL) were added
pyridine (2.21 mmol), (Boc)2O (2.21 mmol) and DMAP (0.17 mmol) at 0
ºC. The reaction mixture was stirred at room temperature until completion
of the reaction (TLC). The mixture was then extracted with ethyl acetate
and washed with brine. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified by
silica gel flash column chromatography (19:1 Petroleum ether: EtOAc).
tert-butyl 3-ethyl-1H-indole-1-carboxylate (1i):
Prepared according to the general procedure and the title compound was
isolated as a colorless gel Yield 82% (0.35 g); TLC Rf 0.40 (19:1,
Petroleum ether: EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.3
Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.38 (s, 1H), 7.33 (t, J = 7.8 Hz, 1H),
7.26 (d, J = 8.8 Hz, 1H), 2.74 (q, J = 7.5 Hz, 2H), 1.70 (s, 9H), 1.36 (t, J =
7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 149.9, 130.7, 124.2, 123.1,
122.2, 121.6, 118.9, 115.2, 83.2, 28.3, 18.1, 13.5; ESI-HRMS: Calculated
for C15H19NNaO2 [M+Na]+ 268.1308, found 268.1313.
Scheme 6. Plausible Mechanism
Conclusions
In summary, we have developed a simple and efficient method
involving cobalt catalysis for the C-2 selective C-H nitration of 3-
substituted indoles under mild reaction conditions. Reaction
proceeds at room temperature and has good functional group
tolerance and afforded the formation of a variety of C-2 nitrated
indole derivatives with moderate to good yield. The removal of
the directing group enhances the synthetic utility of the C-H
functionalization approach. This method is expected to be a
unique approach to access C-2 aminated indoles.
tert-butyl 5-chloro-3-ethyl-1H-indole-1-carboxylate (1j):
Prepared according to the general procedure and the title compound was
isolated as a colorless gel Yield 75% (0.43 g); TLC Rf 0.40 (19:1,
Petroleum ether: EtOAc); 1H NMR (500 MHz, CDCl3): δ 8.06 (s, 1H), 7.51
(d, J = 2.0 Hz, 1H), 7.38 (s, 1H), 7.29 – 7.26 (m, 1H), 2.69 (dq, J = 7.5,
1.3 Hz, 2H), 1.69 (s, 9H), 1.34 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3): δ 147.6, 133.7, 129.7, 129.4, 126.8, 125.3, 120.8, 116.3, 86.5,
27.6, 17.6, 14.2; ESI-HRMS: Calculated for C15H18ClNNaO2 [M+Na]+
302.0918, found 302.0939.
Experimental Section
tert-butyl 3-(2-isopropoxy-2-oxoethyl)-1H-indole-1-carboxylate (1q):
General Methods: All commercially available compounds (Acros, Sigma-
Aldrich, Alfa-Aesar, Merck etc.,) were used without purification. Unless
otherwise noted, all reactions were performed in oven-dried glassware.
All reactions were run under nitrogen atmosphere (or oxygen, where
specified). All solvents used in the reactions were purified before use.
Tetrahydrofuran was distilled from sodium and benzophenone, whereas
dry dichloromethane, dimethylformamide, dioxane, toluene and
Prepared according to the general procedure and the title compound was
isolated as a colorless gel Yield 86% (0.47 g); TLC Rf 0.30 (19:1,
Petroleum ether: EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.1
Hz, 1H), 7.60 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H),
7.28 (d, J = 7.2 Hz, 1H), 5.08 (q, J = 6.4 Hz, 1H), 3.70 (d, J = 2.0 Hz, 2H),
1.69 (s, 9H), 1.32 – 1.22 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 170.6,
149.6, 135.4, 130.1, 124.4, 124.3, 122.5, 119.1, 115.2, 113.4, 83.5, 68.4,
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800036
Chemistry - An Asian Journal
FULL PAPER
31.5, 28.2, 21.8; ESI-HRMS: Calculated for C18H23NNaO4 [M+Na]+
340.1519, found 340.1517.
pressure. The crude product was purified by a silica gel flash column
chromatography to result in the desired product.
tert-butyl 3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (1r):
tert-butyl 3-methyl-2-nitro-1H-indole-1-carboxylate (2a):
o
Prepared according to the general procedure and the title compound was
isolated as a colorless gel Yield 91% (0.39 g); TLC Rf 0.30 (19:1,
Petroleum ether: EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.2
Hz, 1H), 7.60 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H),
7.28 (d, J = 7.2 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.73 (s, 2H), 1.69 (s,
9H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.0, 152.1,
149.6, 130.1, 124.5, 124.3, 122.5, 119.0, 115.2, 113.2, 83.6, 81.0, 61.0,
31.2, 28.2, 14.2; ESI-HRMS: Calculated for C17H21NNaO4 [M+Na]+
326.1363, found 326.1370.
Yield: 72% (56 mg), Physical appearance: Yellow solid, M. p. 81-83 C,
1
TLC Rf 0.50 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
δ 8.05 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.8 Hz,
1H), 7.34 (t, J = 7.6 Hz, 1H), 2.51 (s, 3H), 1.58 (s, 9H); 13C NMR (100
MHz, CDCl3): δ 148.0, 135.6, 129.4, 126.6, 124.0, 121.6, 121.5, 114.7,
85.9, 27.6, 9.6; IR (KBr, cm-1): 2984, 2925, 1748, 1519, 1451, 1311,
1155, 1114, 914, 860, 747; ESI-HRMS: Calculated for C14H16N2NaO4
[M+Na]+ 299.1002, found 299.0998.
tert-butyl 5-bromo-3-methyl-2-nitro-1H-indole-1-carboxylate (2b):
tert-butyl 3-(4-chlorophenethyl)-1H-indole-1-carboxylate (1u):
o
Yield: 71% (64 mg), Physical appearance: Yellow solid, M. p. 73-75 C,
1
Prepared according to the general procedure and the title compound was
isolated as a colorless gel Yield 79% (0.40 g); TLC Rf 0.50 (19:1,
Petroleum ether: EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 8.0
Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.39 – 7.30 (m, 2H), 7.30-7.23 (m, 3H),
7.22 – 7.11 (m, 2H), 3.00 (s, 4H), 1.69 (s, 9H); 13C NMR (100 MHz,
CDCl3): δ 149.8, 140.2, 131.7, 130.5, 129.7, 128.4, 124.3, 122.5, 122.3,
120.1, 118.8, 115.3, 83.4, 34.9, 28.2, 26.8; ESI-HRMS: Calculated for
C21H22ClNNaO2 [M+Na]+ 378.1231, found 378.1253.
TLC Rf 0.50 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
δ 7.94 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.60 (dd, J = 9.0, 2.0
Hz, 1H), 2.45 (s, 3H), 1.57 (s, 10H); 13C NMR (100 MHz, CDCl3): δ 147.6,
134.0, 132.2, 128.1, 127.0, 124.1, 119.9, 117.2, 116.5, 86.5, 27.6, 9.4; IR
(KBr, cm-1): 2915, 2909, 2350, 1739, 1517, 1448, 1378, 1270, 1124,
1055, 866, 811; ESI-HRMS: Calculated for C14H15BrN2NaO4 [M+Na]+
377.0107 and 379.0088, found 377.0134 and 379.0114.
tert-butyl 5-chloro-3-methyl-2-nitro-1H-indole-1-carboxylate (2c):
tert-butyl-3-(3-ethoxy-3-oxopropyl)-5-methoxy-1H-indole-1-
o
carboxylate (1y):
Yield: 66% (56 mg), Physical appearance: Yellow solid, M. p. 88-90 C,
1
TLC Rf 0.50 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
Prepared according to the general procedure and the title compound was
isolated as a white solid Yield 72% (0.36 g), M. p. 100-101 oC, TLC Rf
0.40 (19:1, Petroleum ether:EtOAc). 1H NMR (400 MHz, CDCl3): δ 8.01
(s, 1H), 7.37 (s, 1H), 6.99 (s, 1H), 6.94 (dt, J = 9.0, 2.0 Hz, 1H), 4.19 (q, J
= 7.3, 2H), 3.89 (d, J = 1.6 Hz, 3H), 3.01 (t, J = 7.7 Hz, 2H), 2.77 – 2.68
(m, 2H), 1.67 (s, 9H), 1.28 (t, J = 7.1, 3H); 13C NMR (100 MHz, CDCl3): δ
172.9, 155.7, 131.1, 123.1, 119.2, 116.0, 112.9, 101.6, 83.2, 60.5, 55.7,
33.8, 28.2, 20.3, 14.2; ESI-HRMS: Calculated for C19H25NNaO5 [M+Na]+
370.1625, found 370.1625.
δ 8.00 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.47 (dd, J = 8.9, 2.1
Hz, 1H), 2.46 (s, 3H), 1.57 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 147.6,
133.6, 129.8, 129.6, 127.7, 124.3, 120.9, 120.0, 116.2, 86.5, 27.6, 9.4; IR
(KBr, cm-1): 2981, 2931, 1754, 1524, 1450, 1347, 1270, 1227, 1127, 920,
840, 760, 681; ESI-HRMS: Calculated for C14H15ClN2NaO4 [M+Na]+
333.0613, found 333.0592.
tert-butyl 3,5-dimethyl-2-nitro-1H-indole-1-carboxylate (2d):
o
Yield: 62% (60 mg), Physical appearance: Yellow solid, M. p. 80-82 C,
TLC Rf 0.50 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
1
tert-butyl 3-(2-(dimethylamino)ethyl)-1H-indole-1-carboxylate (1z):
δ 7.91 (d, J = 8.5 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 2.48 (s,
3H), 2.45 (s, 3H), 1.57 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 148.1,
133.9, 133.7, 131.0, 126.7, 121.6, 121.1, 114.5, 85.7, 77.3, 77.2, 77.0,
76.6, 27.6, 21.3, 9.6; IR (KBr, cm-1): 2980, 2927, 1746,1516, 1455, 1372,
1271, 1157, 926, 843, 797, 758,716; ESI-HRMS: Calculated for
C15H18N2NaO4 [M+Na]+ 313.1159, found 313.1178.
Prepared according to the general procedure and the title compound was
isolated as a white solid Yield 86% (0.47 g), M. p. 97-99 oC, TLC Rf 0.30
(19:1, Petroleum ether:EtOAc). 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J =
8.1 Hz, 1H), 7.52 (dt, J = 7.7, 1.0 Hz, 1H), 7.39 (s, 1H), 7.33 – 7.26 (m,
1H), 7.24 – 7.18 (m, 1H), 2.92 – 2.81 (m, 2H), 2.66 (dd, J = 9.2, 6.7 Hz,
2H), 2.35 (s, 6H), 1.65 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 149.7,
130.6, 124.3, 122.6, 122.3, 118.8, 118.7, 115.3, 83.3, 59.2, 45.4, 28.2,
23.3. ESI-HRMS: Calculated for C17H24N2NaO2 [M+Na]+ 311.1730, found
311.1718.
tert-butyl 6-bromo-3-methyl-2-nitro-1H-indole-1-carboxylate (2g):
o
Yield: 72% (65 mg), Physical appearance: Yellow solid, M. p. 73-75 C,
TLC Rf 0.50 (19:1, Petroleum ether: EtOAc); 1H NMR (400 MHz, CDCl3):
δ 8.27 (d, J = 1.5 Hz, 1H), 7.55 – 7.40 (m, 2H), 2.48 (s, 3H), 1.57 (s, 9H);
13C NMR (100 MHz, CDCl3): δ 147.6, 135.9, 127.6, 125.4, 123.3, 122.6,
121.1, 118.0, 86.6, 27.6, 9.5; IR (KBr, cm-1): 2914, 2851, 1745, 1650,
1517, 1448, 1310, 1156, 1018, 856, 745; ESI-HRMS: Calculated for
C14H15BrN2NaO4 [M+Na]+ 377.0107 and 379.0088, found 377.0110 and
379.0086.
General procedure for the Co-catalyzed C-H nitration reaction:
In a Schlenk tube equipped with a stir bar, the substrate (0.129 mmol)
was dissolved in dry THF (1.0 mL). Oxygen was bubbled into the reaction
mixture for 10 min followed by the addition of Co(NO3)2.6H2O (10 mol%),
t-BuNO2 (2.0 equiv) and K2S2O8 (2.0 equiv). The tube was fitted with a
Teflon screw cap under an oxygen flow. The reaction mixture was
allowed to stir at room temperature for 12-24 h and then diluted with
EtOAc and filtered through a pad of Celite. The filtrate was extracted with
EtOAc and washed with NaHCO3 solution. The organic extract was dried
over anhydrous Na2SO4, filtered and concentrated under reduced
tert-butyl 6-chloro-3-methyl-2-nitro-1H-indole-1-carboxylate (2h):
o
Yield: 61% (50 mg), Physical appearance: Yellow solid, M. p. 91-93 C,
1
TLC Rf 0.50 (19:1, Petroleum ether: EtOAc); H NMR (500 MHz, CDCl3):
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800036
Chemistry - An Asian Journal
FULL PAPER
δ 8.13 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.5, 1.8
Hz, 1H), 2.52 (s, 3H), 1.61 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 147.6,
135.7, 135.4, 125.0, 124.9, 122.5, 121.1, 115.0, 86.5, 27.6, 9.5. IR (KBr,
cm-1): 3362, 2927, 2369, 1750, 1653, 1559, 1458, 1370, 1270, 1156,
1125, 820; ESI-HRMS: Calculated for C14H15ClN2NaO4 [M+Na]+
333.0614, found 333.0613.
tert-butyl 3-(3-chlorobenzyl)-2-nitro-1H-indole-1-carboxylate (2n):
Yield: 60% (65 mg), Physical appearance: Pale yellow gel, TLC Rf 0.40
1
(19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3): δ 8.08 (d, J
= 8.7 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.33 – 7.25 (m, 2H), 7.23 – 7.13
(m, 3H), 4.24 (s, 2H), 1.59 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 147.7,
139.5, 135.4, 134.5, 129.9, 129.3, 128.6, 127.0, 126.7, 125.6, 124.3,
121.8, 121.6, 114.9, 86.4, 29.7, 27.6; IR (KBr, cm-1): 3056, 2923, 2852,
2316, 1747, 1647, 1520, 1452, 1305, 1261, 1230, 1112, 849, 764; ESI-
HRMS: Calculated for C20H19ClN2NaO4 [M+Na]+ 409.0926, found
409.0937.
tert-butyl 3-ethyl-2-nitro-1H-indole-1-carboxylate (2i):
o
Yield: 68% (69 mg), Physical appearance: Yellow solid, M. p. 96-97 C,
1
TLC Rf 0.50 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
δ 8.06 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56 – 7.48 (m, 1H),
7.38 – 7.29 (m, 1H), 2.93 (q, J = 7.6 Hz, 2H), 1.58 (s, 9H), 1.33 (t, J = 7.6
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 148.0, 135.6, 129.2, 126.9, 125.7,
124.0, 121.4, 114.9, 85.9, 27.6, 17.7, 14.2; IR (KBr, cm-1): 3645, 3372,
2968, 1739, 1514, 1454, 1253, 1154, 761; ESI-HRMS: Calculated for
C15H18N2NaO4 [M+Na]+ 313.1159, found 313.1183 .
tert-butyl 3-(2-methoxy-2-oxoethyl)-2-nitro-1H-indole-1-carboxylate
(2p):
o
Yield: 70% (70 mg), Physical appearance: Yellow solid, M. p. 70-72 C,
1
TLC Rf 0.40 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
δ 8.07 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.9 Hz,
1H), 7.36 (t, J = 7.6 Hz, 1H), 4.00 (s, 2H), 3.71 (s, 3H), 1.58 (s, 9H); 13C
NMR (100 MHz, CDCl3): δ 169.2, 147.6, 135.3, 129.5, 125.6, 124.4,
121.4, 116.7, 114.8, 86.4, 52.5, 29.9, 27.6; IR (KBr, cm-1): 2991, 2918,
2800, 1751, 1520, 1454, 1300, 1270, 1141, 839, 741; ESI-HRMS:
Calculated for C16H18N2NaO6 [M+Na]+ 357.1057, found 357.1075.
tert-butyl 5-chloro-3-ethyl-2-nitro-1H-indole-1-carboxylate (2j):
Yield: 57% (58 mg), Physical appearance: Yellow gel, TLC Rf 0.50 (19:1,
Petroleum ether: EtOAc); 1H NMR (500 MHz, CDCl3): δ 8.06 (d, J = 8.9
Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 8.9, 2.1 Hz, 1H), 2.90 (q, J
= 7.6 Hz, 2H), 1.61 (s, 9H), 1.37 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 147.6, 133.7, 129.7, 129.3, 126.8, 125.3, 120.8, 116.3, 86.5,
27.6, 17.6, 14.2; IR (KBr, cm-1): 2920, 2845, 2398, 1729, 1554, 1455,
1275, 1158, 1063, 1018, 861. ESI-HRMS: Calculated for
C15H17ClN2NaO4 [M+Na]+ 347.0769, found 347.0759.
tert-butyl
3-(2-isopropoxy-2-oxoethyl)-2-nitro-1H-indole-1-
carboxylate (2q):
o
Yield: 61% (72 mg), Physical appearance: Yellow solid, M. p. 56-58 C,
1
TLC Rf 0.40 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
tert-butyl 3,7-dimethyl-2-nitro-1H-indole-1-carboxylate (2k):
δ 8.06 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 – 7.49 (m, 1H),
7.39 – 7.30 (m, 1H), 5.01 (q, J = 6.30 Hz, 1H), 3.96 (s, 2H), 1.58 (s, 9H),
1.20 (d, J = 6.3 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 168.2, 135.3,
129.4, 125.7, 124.3, 121.4, 117.1, 114.8, 99.9, 86.3, 77.3, 69.3, 30.4,
27.6, 21.7; IR (KBr, cm-1): 2978, 2922, 2852, 1741, 1524, 1454, 1311,
1270, 1155, 841, 750; ESI-HRMS: Calculated for C18H22N2NaO6 [M+Na]+
385.1370, found 385.1347.
Yield: 70% (68 mg), Physical appearance: Yellow solid, M. p. 104-106 oC,
1
TLC Rf 0.50 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
δ 7.53 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz,
1H), 2.61 (s, 3H), 2.57 (s, 3H), 1.60 (s, 9H); 13C NMR (100 MHz, CDCl3):
δ 149.3, 134.2, 131.9, 127.0, 123.6, 123.0, 120.5, 119.7, 86.5, 27.3, 19.6,
10.3; IR (KBr, cm-1): 2914, 2393, 1765, 1644, 1505, 1372, 1254,1230,
1097, 841, 731; ESI-HRMS: Calculated for C15H18N2NaO4 [M+Na]+
313.1159, found 313.1135.
tert-butyl
3-(2-ethoxy-2-oxoethyl)-2-nitro-1H-indole-1-carboxylate
(2r):
o
tert-butyl 3-(4-methoxybenzyl)-2-nitro-1H-indole-1-carboxylate (2l):
Yield: 56% (60 mg), Physical appearance: Yellow solid, M. p. 65-67 C,
1
TLC Rf 0.40 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
δ 8.07 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 – 7.49 (m, 1H),
7.35 (t, J = 7.6 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.99 (s, 2H), 1.58 (s,
9H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 159.6, 139.4,
132.6, 126.9, 124.7, 121.4, 121.4, 112.3, 85.0, 62.9, 13.9; IR (KBr, cm-1):
3289, 2914, 1683, 1504, 1366, 1259, 1231, 1150, 1009, 824, 747; ESI-
HRMS: Calculated for C17H20N2NaO6 [M+K]+ 387.0953, found 387.0953.
Yield: 65% (61 mg), Physical appearance: Pale yellow gel, TLC Rf 0.40
(19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3): δ 8.06 (d, J
1
= 8.5 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.52 – 7.45 (m, 1H), 7.30 – 7.25
(m, 1H), 7.20 (d, J = 8.5 Hz, 2H), 6.80 (t, J = 8.7 Hz, 2H), 4.20 (s, 2H),
3.75 (s, 3H), 1.59 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 158.4, 147.8,
135.5, 129.5, 129.1, 125.9, 124.1, 123.1, 122.0, 114.9, 114.1, 86.1, 55.2,
29.2, 27.6; IR (KBr, cm-1): 2941, 2850, 1671, 1540, 1450, 1161, 1055,
815, 728; ESI-HRMS: Calculated for C21H22N2NaO5 [M+Na]+ 405.1421,
found 405.1449.
tert-butyl 3-(4-chlorophenethyl)-2-nitro-1H-indole-1-carboxylate (2u):
Yield: 62% (68 mg), Physical appearance: Yellow gel, TLC Rf 0.40 (19:1,
Petroleum ether: EtOAc); 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 8.7
Hz, 1H), 7.58 – 7.48 (m, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.31,
2H), 7.11 (d, J = 8.3 Hz, 2H), 3.17 (m, 2H), 2.97 (m, 2H), 1.58 (s, 9H);
13C NMR (100 MHz, CDCl3): δ 147.9, 139.0, 135.5, 132.2, 129.7, 129.3,
128.6, 125.7, 124.2, 124.1, 121.3, 114.9, 86.1, 35.2, 27.6, 26.5; IR (KBr,
cm-1): 2973, 2930, 1749, 1519, 1446, 1353, 1311, 1258, 1154,1114,1013,
839, 763; ESI-HRMS: Calculated for C21H21ClN2NaO4 [M+Na]+ 423.1082,
found 423.1107.
tert-butyl 3-(4-chlorobenzyl)-2-nitro-1H-indole-1-carboxylate (2m):
Yield: 62% (68 mg), Physical appearance: Pale yellow gel, TLC Rf 0.40
1
(19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3): δ 8.07 (d, J
= 8.7 Hz, 1H), 7.51 (dd, J = 8.3, 5.8 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.25
– 7.19 (m, 4H), 4.23 (s, 2H), 1.59 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
147.7, 136.0, 135.4, 132.6, 129.8, 129.3, 128.8, 127.8, 125.6, 124.3,
121.8, 114.9, 86.4, 29.4, 27.6; IR (KBr, cm-1): 2981, 2932, 2827, 2316,
1792, 1655, 1510, 1452, 1300, 1241, 1201, 1042, 807, 725; ESI-HRMS:
Calculated for C20H19ClN2NaO4 [M+Na]+ 409.0926, found 409.0938.
tert-butyl 2-nitro-3-phenethyl-1H-indole-1-carboxylate (2v):
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800036
Chemistry - An Asian Journal
FULL PAPER
Yield: 55% (51 mg), Physical appearance: Pale yellow gel, TLC Rf 0.40
(19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3): δ 8.06 (d, J
Yield: 76% (62 mg), Physical appearance: Yellow solid, M. p. 105-107 oC,
TLC Rf 0.30 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
1
1
= 8.4 Hz, 1H), 7.57 – 7.48 (m, 2H), 7.34 – 7.25 (m, 3H), 7.23 – 7.16 (m,
3H), 3.24 – 3.15 (m, 2H), 2.99 (m, 2H), 1.58 (s, 9H); 13C NMR (100 MHz,
CDCl3): δ 147.9, 140.6, 135.5, 129.2, 128.5, 128.4, 126.4, 125.9, 124.7,
124.0, 121.4, 114.8, 86.0, 35.9, 29.7, 27.6, 26.6; IR (KBr, cm-1): 2973,
2395, 2350, 1740, 1641, 1519, 1371, 1156, 1042, 755; ESI-HRMS:
Calculated for C21H22N2NaO4 [M+Na]+ 389.1472, found 389.1493.
δ 9.07 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.41 (d, J
= 8.3 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H), 2.75 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 133.7, 128.6, 127.2, 122.1, 121.6, 118.3, 117.2, 112.1, 10.2; IR
(KBr, cm-1): 3269, 3058, 2919, 2398, 1617, 1447, 1288, 1152, 1047, 735,
592; ESI-HRMS: Calculated for C9H8N2NaO2 [M+Na]+ 199.0472, found
199.0478.
tert-butyl 3-(3-ethoxy-3-oxopropyl)-2-nitro-1H-indole-1-carboxylate
3-ethyl-2-nitro-1H-indole (7i):
(2w):
o
Yield: 89% (75 mg), Physical appearance: Yellow solid, M. p. 89-91 C,
TLC Rf 0.30 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
1
Yield: 68% (66 mg), Physical appearance: Yellow solid, M. p. 101-103 oC,
TLC Rf 0.40 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
1
δ 9.07 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.42 (d, J
= 8.4 Hz, 1H), 7.26 (t, J = 7.7Hz, 1H), 3.24 (q, J = 7.6 Hz, 2H), 1.35 (t, J
= 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 133.8, 128.5, 126.4, 123.4,
122.0, 121.6, 112.1, 18.0, 14.0; IR (KBr, cm-1): 3239, 2963, 2855, 1618,
1549, 1457, 1335, 1291, 1150, 1082, 765; ESI-HRMS: Calculated for
C10H10N2NaO2 [M+Na]+ 213.0641, found 213.0634.
δ 8.05 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.58 – 7.48 (m, 1H),
7.39 – 7.31 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.23 (t, J = 7.6 Hz, 2H),
2.74 (t, J = 7.6 Hz, 2H), 1.58 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 172.1, 147.8, 135.5, 129.4, 125.6, 124.2, 123.5,
121.6, 114.8, 86.2, 60.8, 33.9, 27.6, 19.7, 14.1; IR (KBr, cm-1): 2978,
2930, 1741, 1642, 1520, 1370, 1267, 1227, 1114, 1039, 840, 747; ESI-
HRMS: Calculated for C18H22N2NaO6 [M+Na]+ 385.1370, found 385.1393.
3-benzyl-2-nitro-1H-indole (7o):
o
tert-butyl 3-(3-methoxy-3-oxopropyl)-2-nitro-1H-indole-1-carboxylate
(2x):
Yield: 87% (81 mg), Physical appearance: Yellow solid, M. p. 85-87 C,
1
TLC Rf 0.30 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
δ 9.17 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.43 (d, J
= 8.4 Hz, 1H), 7.33 (d, J = 7.7 Hz, 2H), 7.31 – 7.25 (m, 2H), 7.25 – 7.18
(m, 2H), 4.61 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 138.8, 133.7, 128.6,
128.6, 128.5, 126.8, 126.4, 122.5, 122.0, 119.3, 112.2, 30.3; IR (KBr, cm-
1): 3358, 3114, 2919, 2851, 2320, 1643, 1536, 1120, 1047, 756; ESI-
HRMS: Calculated for C15H12N2NaO2 [M+Na]+ 275.0800, found 275.0791.
o
Yield: 65% (63 mg), Physical appearance: Yellow solid, M. p. 90-92 C,
TLC Rf 0.40 (19:1, Petroleum ether: EtOAc); 1H NMR (400 MHz, CDCl3):
δ 8.05 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.9 Hz,
1H), 7.35 (t, J = 7.6 Hz, 1H), 3.65 (s, 3H), 3.23 (t, J = 7.6 Hz, 2H), 2.76 (t,
J = 7.6 Hz, 2H), 1.58 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 172.5, 147.8,
135.5, 129.4, 125.5, 124.2, 123.4, 121.5, 114.8, 86.2, 51.8, 33.7, 27.6,
19.7; IR (KBr, cm-1): 2920, 2845, 1742, 1520, 1450, 1304,1251, 1113,
1042, 835, 747; ESI-HRMS: Calculated for C17H20N2NaO6 [M+Na]+
317.1214, found 317.1223.
Ethyl 3-(5-methoxy-2-nitro-1H-indol-3-yl)propanoate (7y):
o
Yield: 94% (85 mg), Physical appearance: Yellow solid, M. p. 93-95 C,
1
TLC Rf 0.30 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
tert-butyl
carboxylate (2y):
3-(3-ethoxy-3-oxopropyl)-5-methoxy-2-nitro-1H-indole-1-
δ 8.21 (s, 1H), 7.43 (dd, J = 8.9, 1.8 Hz, 1H), 7.17 (bs, 1H), 6.98 (d, J =
8.8 Hz, 1H), 4.12 (q, J = 8.0 Hz, 2H), 3.96 (s, 3H), 2.94 (t, J = 8.0 Hz, 2H),
2.60 (t, J = 8.0 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 173.0, 145.6, 132.7, 126.1, 124.2, 114.0, 113.1, 108.8, 60.3,
58.0, 34.8, 20.3, 14.1; IR (KBr, cm-1): 3216, 3094, 2919, 1472, 1302,
1204, 1075, 1029, 862, 795; ESI-HRMS: Calculated for C14H16N2O5
[M+H]+ 293.1127, found 293.1126.
o
Yield: 60% (71mg), Physical appearance: Yellow solid, M. p. 100-102 C
TLC Rf 0.40 (19:1, Petroleum ether: EtOAc); H NMR (400 MHz, CDCl3):
1
δ 8.23 (d, J = 9.3 Hz, 1H), 7.42 (s, 1H), 7.01 (d, J = 9.2 Hz, 1H), 4.12 (q,
J = 7.1 Hz, 2H), 3.92 (s, 3H), 2.82 (t, J = 7.3 Hz, 2H), 2.57 (t, J = 7.2 Hz,
2H), 1.63 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
172.5, 149.0, 146.9, 133.1, 131.0, 126.6, 122.2, 117.9, 116.6, 109.6,
84.4, 60.5, 57.3, 33.9, 28.1, 20.0, 14.2; IR (KBr, cm-1): 2980, 2369, 1735,
1588, 1531, 1435, 1373, 1276, 1221, 1158, 1075, 853, 765; ESI-HRMS:
Calculated for C19H24N2NaO7 [M+Na]+ 415.1476, found 415.1486.
2-nitro-3-phenethyl-1H-indole (7v):
Yield: 97% (73 mg), Physical appearance: Yellow solid, M. p. 110-112 oC,
TLC Rf 0.30 (19:1, Petroleum ether: EtOAc); 1H NMR (400 MHz, CDCl3)
δ 9.12 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.41 (d, J
= 8.3 Hz, 1H), 7.34 – 7.25 (m, 4H), 7.25 – 7.16 (m, 2H), 3.55 – 3.44 (m,
2H), 3.02 (dd, J = 9.3, 6.7 Hz, 2H). 13C NMR (101 MHz, CDCl3) 13C NMR
(100 MHz, CDCl3) δ 141.1, 133.6, 128.6, 128.5, 128.4, 126.6, 126.2,
122.0, 121.7, 120.8, 112.1, 35.8, 27.0; ESI-HRMS: Calculated for
C16H14N2O2 [M+H]+ 267.1133, found 267.1124.
General procedure for Boc-deprotection:
To a solution of 2-nitro-N-Boc indole (0.3 mmol) in CH2Cl2 (3 mL), was
added TFA (0.1 mmol) dropwise at 0 C under argon atmosphere,
following which the cooling bath was removed and the mixture was
stirred at room temperature for 1-2 h. Upon completion of the reaction,
the reagent and the solvent were removed under reduced pressure and
the residue was diluted with CH2Cl2. The organic layer was washed with
NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by silica gel flash
column chromatography (9:1 Petroleum ether: EtOAc).
The deuterated substrate 1a[D1] was prepared according to the
procedure reported in literature.[25]
Acknowledgements
3-methyl-2-nitro-1H-indole (7a):
SERB-India
(SB/S1/OC-10/2014)
and
CSIR-India
(02(205)/14/EMR-II) are gratefully acknowledged for the
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800036
Chemistry - An Asian Journal
FULL PAPER
(f) B. Majhi, D. Kundu, B. C. Ranu, Chem. - Eur. J. 2014, 20, 9862-
9866; (g) J. Dong, B. Jin, P. Sun, Org. Lett. 2014, 16, 4540-4542; (h) Y.
Liu, W. Zhang, J. Zhang, S. Ren, J. Org. Chem. 2014, 79, 11508-
11516; (i) D. Katayev, K. F. Pfister, T. Wendling, L. J. Gooßen, Chem. -
Eur. J. 2014, 20, 9902-9905; (j) Y.-F. Liang, X. Li, X. Wang, Y. Yan, P.
Feng, N. Jiao, ACS Catal. 2015, 5, 1956-1963; (k) P. Sadhu, S. K. Alla,
T. Punniyamurthy, J. Org. Chem. 2015, 80, 8245-8253; (l) G. G. Pawar,
A. Brahmanandan, M. Kapur, Org. Lett. 2016, 18, 448-451; (m) Z. Fan,
J. Li. H. Lu. D.-Y. Wang, C. Wang. M. Uchiyama. A. Zhang. Org. Lett.
2017, 19, 3199-3202.
research funding. P.S. thanks IISERB for a Research Fellowship.
We thank the CIF, IISERB for the spectral data and Mr. Lalit
Mohan Jha, IISERB for the X-ray data. We also thank the
Director, IISERB, for funding and infrastructure facilities.
Keywords: Indoles • Weak coordinating groups •
C(sp2)-H nitration • Removable directing group •
Cobalt catalysis.
[8] (a) C. J. Whiteoak, O. Planas, A. Company, X. Ribas, Adv. Synth. Catal.
2016, 358, 1679-1688; (b) V. Botla, D. V. Ramana, B. Chiranjeevi, M.
Chandrasekharam, Chemistry Select. 2016, 1, 3974-3978; (c) D. N.
Rao, Sk. Rasheed, G. Raina, Q. N. Ahmed, C. K. Jaladanki, P. V.
Bharatam, P. Das, J. Org. Chem. 2017, 82, 7234-7244.
[1]
For some selected reviews on directed C-H functionalization, see: (a) L.
Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem., Int. Ed. 2009, 48,
9792-9826; Angew. Chem. 2009, 121, 9976; (b) X. Chen, K. M. Engle,
D.-H. Wang, J.-Q. Yu, Angew. Chem., Int. Ed. 2009, 48, 5094-5115;
Angew. Chem. 2009, 121, 5196; (c) D. A. Colby, R. G. Bergman, J. A.
Ellman, Chem. Rev. 2010, 110, 624-655; (d) T. W. Lyons, M. S.
Sanford, Chem. Rev. 2010, 110, 1147-1169; (e) J. Wencel-Delord, T.
Dröge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40, 4740-4761; (f) L.
Ackermann, Chem. Rev. 2011, 111, 1315-1345; (g) S. H. Cho, J. Y.
Kim, J. Kwak, S. Chang, Chem. Soc. Rev. 2011, 40, 5068-5083; (h) L.
McMurry, F. O’Hara, M. J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885-
1898; (i) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res.
2012, 45, 788-802; (j) J. Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5,
369-375; (k) L. Ackermann, Acc. Chem. Res. 2014, 47, 281-295; (l) Q.-
Z. Zheng, N. Jiao, Tetrahedron Lett. 2014, 55, 1121-1126; (m) G. Y.
Song, X. W. Li, Acc. Chem. Res. 2015, 48, 1007-1020; (n) Z. Chen, B.
Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang, Org. Chem. Front. 2015, 2,
1107-1295; (o) J. Jiao, K. Murakami, K. Itami, ACS Catal. 2016, 6, 610-
633; (p) J. A. Leitch, Y. Bhonoah, C. G. Frost, ACS Catal. 2017, 7,
5618-5627; (q) H. M. L. Davies, D. Morton, ACS Cent. Sci. 2017, 3,
936-943; (r) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017, 117, 9247-
9301; (s) K. Murakami, S. Yamada, T. Kaneda, K. Itami, Chem. Rev.
2017, 117, 9302-9332; (t) R. Das, G. S. Kumar, M. Kapur, Eur. J. Org.
Chem. 2017, 5439-5459.
[9]
For some recent reviews and select examples of Co-catalyzed C–H
functionalization, see: (a) K. Gao, N. Yoshikai, Acc. Chem. Res. 2014,
47, 1208-1219; (b) B. Su, Z.-C. Cao, Z.-J. Shi, Acc. Chem. Res. 2015,
48, 886-896; (c) M. Moselage, J. Li, L. Ackermann, ACS Catal. 2016, 6,
498-525; (d) D. Wei, X. Zhu, J.-L. Niu, M.-P. Song, ChemCatChem,
2016, 8, 1242-1263; (e) T. T. Nguyen, L. Grigorjeva, O. Daugulis, ACS
Catal. 2016, 6, 551-554; (f) T. Yoshino, S. Matsunaga, Adv. Synth.
Catal. 2017, 359, 1245-1262; (g) Y. Li, F. Qian, M. Wang, H. Lu, G. Li,
Org. Lett. 2017, 19, 5589-5592.
[10] For select examples, see: (a) A. Kulkarni, O. Daugulis, Synthesis 2009,
4087-4109; (b) D. Koley, O. C. ColoO´n, S. N. Savinov, Org. Lett. 2009,
11, 4172-4175; (c) N. Yoshikai, Synlett 2011, 1047-1051; (d) J.
Yamaguchi, K. Muto, K. Itami, Eur. J. Org. Chem. 2013, 19-30; (e ) Y. Ji,
H. Yan, Q. Jiang, Eur. J. Org. Chem. 2015, 2051-2060; (f) W. Liu, L.
Ackermann, ACS Catal. 2016, 6, 3743-3752; (g) G. Pototschnig, N.
Maulide, M. Schnerch. Chem. -Eur. J. 2017, 23, 9206-9232; (h) Li. Wan,
K. Qiao, X. Yuan, M.-W. Zheng, B.-B. Fan, Z. C. Di, D. Zhang, Z. Fang,
K. Guo, Adv. Synth. Catal. 2017, 359, 2596-2604; (i) K. Qiao, X. Yuan,
L. Wan, M.-W. Zheng, D. Zhang, B.-B. Fan, Z.-C. Di, Z, Fang, K. Guo
Green Chem. 2017, 19, 5789–5793.
[2]
For selected reviews on indoles and their syntheses, see: (a) G. W.
Gribble, J. Chem. Soc. Perkin Trans.1 2000, 1045-1075; (b) G. R.
Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875-2911; (c) S.
Cacchi, G. Fabrizi, Chem. Rev. 2011, 111, PR215-PR283; (d) A. H.
Sandtorv, Adv. Synth. Catal. 2015, 357, 2403-2435; For some recent
contributions from our group, see: (e) V. K. Tiwari, N. Kamal, M. Kapur,
Org. Lett. 2015, 17, 1766-1769; (f) A. K. Kale, G. S. Kumar, A. R. K.
Mangadan, M. Kapur, Org. Lett. 2015, 17, 1324-1327; (g) A. K. Kale, G.
S. Kumar, M. Kapur, Org Biomol. Chem. 2015, 13, 10995-11002; (h) G.
S. Kumar, M. Kapur, Org. Lett. 2016, 18, 1112-1115.
[11] Crystal Structure submitted to Cambridge Crystallographic Data Centre.
CCDC deposition numbers: 1575446 (compound 2b) and 1576560
(compound 3a) respectively.
[12] In the presence of oxygen, the autoxidation of nitrogen monoxide results
in nitrogen dioxide: (a) S. Goldstein, G. Czapski, J. Am. Chem. Soc.
1995, 117, 12078-12084; (b) L. Grossi, S. Strazzari, J. Org. Chem.
1999, 64, 8076-8079; (c) B. Galliker, R. Kissner, T.; Nauser, Koppenol,
W. H. Chem. -Eur. J. 2009, 15, 6161-6168.
[13] A. Yamamoto, M. Nishiura, Y. Yang, Z. Hou, Organometallics DOI:
10.1021/acs.organomet.7b00526.
[3]
(a) H. Feuer, A. T. Nielson, Nitro Compounds: Recent Advances in
Synthesis and Chemistry; VCH: New York, 1990; (b) N. Ono, The Nitro
Group in Organic Synthesis; Wiley−VCH: Weinheim, 2001.
[14] For a review on cyclometallation using d-block transition metals, see: M.
Albrecht, Chem. Rev. 2010, 110, 576-623.
[15] R. Beaud, R. Guillot, C. Kouklovsky, G. Vincent, Chem. -Eur. J. 2014,
20, 7492-7500.
[4]
[5]
(a)G. A. Olah, Acc. Chem. Res. 1971, 4, 240-248; (b) R. Taylor,
Electrophilic Aromatic Substitution; Wiley: Chichester, 1990.
[16] G. Shao, G. Shi, Y. Zhang, S. Pan, X. Guan, Org. Lett. 2015, 17, 2652-
2655.
(a) G. A. Olah, R. Malhotra, Narang, S. C. Nitration: Methods and
Mechanisms; VCH: Weinheim, 1989; (b) G. A. Olah, S. J. Kuhn, J. Am.
Chem. Soc. 1962, 84, 3684-3687; (c) G. A. Olah, G. K. S. Prakash, Q.
Wang, X. Li, in Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed. Wiley: Chichester, 1995; Vol. 6; (d) S. Salzbrunn, J.
Simon, G. K. S. Prakash, N. A. Petasis, G. A. Olah, Synlett 2000, 1485-
1487; (e) H. B. Sun, R. Hua, Y. Yin, J. Org. Chem. 2005, 70, 9071-9073.
For a review on synthesis of nitro compounds, see: G. Yan, M. Yang,
Org. Biomol. Chem. 2013, 11, 2554-2566.
[17] W. Chen, Y. Xia, L. Lin, X. Yuan, S. Guo, X. Liu, X. Feng, Chem. -Eur. J.
2015, 21, 15104-15107.
[18] T. Tomakinian, R. Guillot, C. Kouklovsky, G. Vincent, Angew. Chem., Int.
Ed. 2014, 53, 11881-11885; Angew. Chem. 2014, 126, 12075.
[19] S. Ferro, D. L. Luca, L. S. Surdo, F. Morreale, F. Christ, Z. Debyser. R.
Gitto, A. Chimirri, Bioorg. Med. Chem. 2014, 22, 2269-2279.
[20] R. Cano, M. Yus, D. J. Ramón, Tetrahedron Lett. 2013, 54, 3394-3397.
[21] A. K. Putra, K. Takigawa, H. Tanaka, Y. Ito, Y. Oe, T. Ohta, Eur. J. Org.
Chem. 2013, 6344-6354.
[6]
[7] (a) L. Zhang, Z. Liu, H. Li, G. Fang, B.-D. Barry, T. A. Belay, X. Bi, Q. Liu,
Org. Lett. 2011, 13, 6536-6539; (b) W. Zhang, S. Lou, Y. Liu, Z. Xu, J.
Org. Chem. 2013, 78, 5932-5948; (c) F. Xie, Z. S. Qi, X. W. Li, Angew.
Chem., Int. Ed. 2013, 52, 11862-11866; Angew. Chem. 2013, 125,
12078; (d) W. Zhang, S. Lou, Y. Liu, Z. Xu, J. Org. Chem., 2013, 78,
5932-5948; (e) W. Zhang, Y. Liu, Eur. J. Org. Chem. 2014, 5827-5835;
[22] Z. Časar, D. Bevk, J. Svete, B. Stanovnik, Tetrahedron 2005, 61, 7508-
7519.
[23] W. L. Chen, Y. R. Gao, S. Mao, Y. L. Zhang, Y. F. Wang, Y. Q. Wang,
Org. Lett. 2012, 14, 5920-5923.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800036
Chemistry - An Asian Journal
FULL PAPER
[24] E. K. Olsen, E. Hansen, L.W. K. Moodie, J. Isaksson, K. Sepčić, M.
Cergolj, J. Svenson, J. H. Andersen, Org. Biomol. Chem. 2016, 14,
1629-1640.
[25] V. K. Tiwari, N. Kamal, M. Kapur, Org. Lett. 2015, 17, 1766.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

10.1002/asia.201800036
Chemistry - An Asian Journal
FULL PAPER
FULL PAPER
Paridhi Saxena and Manmohan Kapur*
Page No. – Page No.
Cobalt-Catalyzed C-H Nitration of
Indoles Employing a Removable
Directing Group
A mild and efficient C(sp2)-H nitration of 3-substituted indoles, using the
economical and non-toxic cobalt nitrate hexahydrate [Co(NO3)2.6H2O] as catalyst
and tert-butyl nitrite (TBN) as the nitro source, is being reported. This approach
provides a unique methodology involving a site-selective C-N bond formation for
t
preparation of C-2 substituted nitro indoles. Utilization of the Boc as the removable
directing group enhances the synthetic utility of the method.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.