Regioselective C5 nitration of N-protected indolines using ferric nitrate under mild conditions

Article abstract of DOI:10.1080/00397911.2019.1580745

An efficient and facile process has been developed for the regioselective C5 nitration of the N-protected indolines using ferric nitrate as the nitrating reagents. The reaction proceeded smoothly in moderate to excellent yields with high efficiency and broad substrate scope under mild conditions. In addition, the synthesized nitration products can be further transformed to 5-nitroindolines and C5-nitroindole derivatives. The method is operationally simple, efficient, and might have potential application in industry production.

Full text of DOI:10.1080/00397911.2019.1580745

Synthetic Communications
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Regioselective C5 nitration of N-protected
indolines using ferric nitrate under mild conditions
Dandan Li, Yimeng Chen, Mengya Ma, Yanling Yu, Zhenzhen Jia, Penghui Li &
Zhiyu Xie
To cite this article: Dandan Li, Yimeng Chen, Mengya Ma, Yanling Yu, Zhenzhen Jia, Penghui Li
& Zhiyu Xie (2019): Regioselective C5 nitration of N-protected indolines using ferric nitrate under
mild conditions, Synthetic Communications, DOI: 10.1080/00397911.2019.1580745
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https://doi.org/10.1080/00397911.2019.1580745
Regioselective C5 nitration of N-protected indolines using
ferric nitrate under mild conditions
Dandan Li, Yimeng Chen, Mengya Ma, Yanling Yu, Zhenzhen Jia, Penghui Li, and
Zhiyu Xie
School of Chemistry and Chemical Engineering, Xuchang University, Xuchang, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 29 November 2018
An efficient and facile process has been developed for the regiose-
lective C5 nitration of the N-protected indolines using ferric nitrate
as the nitrating reagents. The reaction proceeded smoothly in mod-
erate to excellent yields with high efficiency and broad substrate
scope under mild conditions. In addition, the synthesized nitration
products can be further transformed to 5-nitroindolines and C5-nitro-
indole derivatives. The method is operationally simple, efficient, and
might have potential application in industry production.
KEYWORDS
Indolines; C5 nitration; ferric
nitrate; nitrating reagents;
5-nitroindolines
GRAPHICAL ABSTRACT
Introduction
Nitroarenes are widely utilized in various fields such as pharmaceuticals, explosives,
dyes, and materials.[1] Furthermore, aromatic nitro compounds are important building
blocks for organic synthesis because they can be easily transformed into amines and
ketones.[1d,1e,2] Traditionally, the classical approach to synthesize the aromatic nitro
compounds is the direct electrophilic nitration, using conc. HNO3–H2SO4, conc. HNO3-
mixed anhydrides, and NaNO3–TFA as the nitrating reagents.[3] However, these proc-
esses often suffer from poor selectivity, harsh reaction conditions, and limited functional
group tolerance.[4] Moreover, undesirable by-products and large quantities of hazardous
acids are generated through these procedures. Therefore, it remains a challenge to
develop new strategy for the direct nitration reaction.
Nitroindolines and its derivatives have been used as photolabile protective groups,
photochemically activated coupling reagents.[5] Some of nitro-substituted indoles have
potent activity against tuberculosis.[6] Thus, the synthesis of nitroindolines continues to
be attractive in the synthetic community due to the unavailability of suitable methods.
CONTACT Dandan Li
dandanli2015@outlook.com; Zhiyu Xie
zhiyu0823@163.com
School of Chemistry and
Chemical Engineering, Xuchang University, Xuchang 461000, P. R. China.
Supplemental data for this article is available online on the publisher's website.
ß 2019 Taylor & Francis Group, LLC

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D. LI ET AL.
Figure 1. C5 nitration of N-acetyl indoline. (a) Our regioselective C5 nitration approach under mild
conditions. (b) Mal’s mono-nitration approach C–H nitration.
In recent years, ipso-nitration[7] and transition-metal-catalyzed C ꢀ H bond functionali-
zation reactions[1f,8] have been developed to achieve the aromatic nitro compounds.
Meanwhile, various metal nitrate salts have emerged as new nitrating agents, such as
AgNO3,[9] Bi(NO3)3ꢁ5H2O,[10] Fe(NO3)3ꢁ9H2O,[11] Ca(NO3)2,[12] Ni(NO3)2ꢁ6H2O,[13]
and so on. Most recently, Mal group[14] reported C–H mono-nitration of indolines with
a complex systems (Figure 1a). Inspired by these elegant studies and our interest in
C ꢀ H bond functionalization,[15] herein, we report the highly regioselective nitration of
indolines only with the cheap metal nitrate salts to afford C5-nitroindolines (Figure 1b).
Results and discussion
At the outset of our study, N-acetyl indoline (1a) was chosen as a model substrate to
optimize the reaction conditions, including various nitrating agents, solvents, and tem-
perature (Table 1). It is known that iron is a nontoxic and inexpensive metal, and iron
nitrate nonahydrate (Fe(NO3)3ꢁ9H2O) can generate nitrogen dioxide radical (NO2ꢁ)
through the thermal decomposition.[12] In general, Fe(NO3)3ꢁ9H2O has been used as a
clean nitration source frequently. Therefore, in our initial study, we first chose
Fe(NO3)3ꢁ9H2O as nitrating reagent. To our delight, the reaction proceeded smoothly,
giving the C5 nitration product 2a in 89% yield at 40 ꢂC under an air atmosphere for
5 h (Table 1, entry 1). Then, we examined various metal nitrate salts including
Bi(NO3)3ꢁ5H2O, AgNO3, Cu(NO3)2ꢁ3H2O, Co(NO3)2ꢁ6H2O, Ce(NH4)2(NO3)6, and
KNO3. However, only Cu(NO3)2ꢁ3H2O gave 8% yield, the remaining agents could not
react (Table 1, entries 2–7). Other nitrating agents such as NH4NO3, NaNO2[16], and
tert-butyl nitrite (TBN) were also explored, but both of them could not give a better
yield than Fe(NO3)3ꢁ9H2O (Table 1, entries 8–10). Moreover, when the temperature was
dropped from 40 ꢂC to room temperature, the yield of 2a became lower even if the
reaction time was prolonged to 12 h (Table 1, entry 11). In addition, the effect of solv-
ent was also explored. Disappointingly when 1,2-dichloroethane (DCE), CH2Cl2, toluene
(PhMe), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and 1,4-dioxane
were employed as the solvent, but all of them proved to be deleterious to the reaction

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Table 1. Optimization of reaction conditions.a
Entry
[NO2] source (equiv.)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
Fe(NO3)3ꢁ9H2O (0.5eq.)
Bi(NO3)3ꢁ5H2O (0.5eq.)
AgNO3 (1.5eq.)
Cu(NO3)2ꢁ3H2O (0.5eq.)
Co(NO3)2ꢁ6H2O (0.5eq.)
Ce(NH4)2(NO3)6 (0.25eq.)
KNO3 (1.5eq.)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
CH2Cl2
PhMe
DMF
DMSO
1,4-dioxane
89%
trace
0%
8%
0%
0%
0%
0%
31% (48%)
58%
72%
66%
59%
0%
NH4NO3 (1.5 eq.)
NaNO2 (1.5 eq.)
TBN (1.5eq.)
9c
10
11d
12
13
14
15
16
17
Fe(NO3)3ꢁ9H2O (0.5eq.)
Fe(NO3)3ꢁ9H2O (0.5eq.)
Fe(NO3)3ꢁ9H2O (0.5eq.)
Fe(NO3)3ꢁ9H2O (0.5eq.)
Fe(NO3)3ꢁ9H2O (0.5eq.)
Fe(NO3)3ꢁ9H2O (0.5eq.)
Fe(NO3)3ꢁ9H2O (0.5eq.)
0%
0%
0%
aUnless otherwise specified, all reactions were carried out with 0.3 mmol of 1a, and nitrating agent in 3 mL of solvent
under an air atmosphere at 40 ꢂC for 5 h.
bIsolated yield.
c1.5 eq. CF3CO2H was added; when CF3CO2H (1 mL) and CH3CN (2 mL) were as solvent, the yield was given in
parentheses.
dAt 25 ꢂC, 12 h.
(Table 1, entries 12–17). Therefore, the use of N-acetyl indoline 50 mol% of
Fe(NO3)3ꢁ9H2O at 40 ꢂC in CH3CN was chosen as the optimal reaction conditions.
With the optimized reaction conditions in hand, we started to investigate the scope
and limitation of the reaction. The reaction results are listed in Table 2. Indolines 1a–z
with various protected substituents could afford the nitrated products 2a–z in moderate
to excellent yields. Substrates 1a–g bearing formyl, acetyl, isopropanoyl, tert-butyryl,
pivaloyl, cyclopropionyl, and cyclohexanoyl groups reacted smoothly to give the corre-
sponding products 2a–g in 81–95% yields. It should be noted that indoline 1h bearing
the strong electron-withdrawing chloroacetyl group could also be functionalized to bring
out the desired product, albeit at a relatively low yield with 5% Cu(OTf)2 as catalyst.
When 1i was employed as the substrate, a good yield (74%) was obtained for the C5-
nitrated product (2i). Gratifyingly, N-benzoyl indolines containing electron-neutral sub-
stituent (H and Me) or halogen atoms such as F, and Cl reacted smoothly and led to
corresponding products (2j–2m, 2o–2p) in 59–85% yields, albeit in a slightly low yield
even with more solvent and a temperature rise. However, N-benzoyl indoline (1n) bear-
ing the electron-donating p-OMe group only bring out the target product in 37% yield
with the generation of other unknown by-products. To expand the substrate scope of
the reaction, the optimized reaction conditions were applied to a wide range of indo-
lines with different substituents in the pyrrolidine moiety. To our delight, when indo-
lines substituted with methyl were chosen as the reactants, they could react smoothly to

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D. LI ET AL.
Table 2. Substrate scope of the C5 nitration reaction of N-protected
indolines.a,b
aUnless otherwise indicated, all reactions were carried out with 0.3 mmol of indolines,
0.15 mmol of Fe(NO3)3ꢁ9H2O, in CH3CN (3 mL) at 40 ꢂC.
bIsolated yield.
c5 mol% Cu(OTf)2 was used.
dCH3CN (6 mL), at 60 ꢂC.
eAt 60 ꢂC.

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Table 3. Substrate scope of the nitration reaction of N-protected indolines.a,b
aUnless otherwise indicated, all reactions were carried out with 0.3 mmol of indolines, 0.15 mmol of
Fe(NO3)3ꢁ9H2O, in CH3CN (3 mL) at 40 ꢂC.
bIsolated yield.
give the corresponding products 2q, 2r, and 2s in 70–90% yields. Subsequently, N-acetyl
indoline 1t bearing the electron-withdrawing CO2Me group could also afford the
desired product, albeit in a relatively low yield.
Encouraged by the above results, we began to explore the scope of substitution on
the aromatic ring of indoline. Indoline with 7-Me group could proceed smoothly to
give the target molecules 2u in 86% yield, surprisingly, when indoline with 7-OMe
group also afford the C5 nitration product in 70% yield. Meanwhile, 4-Me group on the
phenyl ring of indoline 1w was employed as the substrate, a mixed products 2w and
2w’ (1:5) were obtained probably due to the steric hindrance. Similarly, substrates bear-
ing 4-F group was compatible with this nitration protocol, generating a mixed products
2x and 2x’ (1:2). Additionally, 1-(6-chloroindolin-1-yl)ethanone 1y was also tolerant in
this transformation, giving the corresponding product in 22% yield. Compared with
chloroacetyl group, the N,N-dimethyl formyl group could afford the target product 2z
in 88% yield under the same experimental conditions.
In addition, other N-substituted substrates were also examined (Table 3). N-protected
substituents such as Boc and Ts also could be applied to afford the desired products
(2aa and 2ab). However, when 1-methylindoline, 1-phenylindolin-2-one, and 1-acetyl-6-
chloroindolin-2-one were employed as reactant, respectively, either no or trace amounts
of products were formed. Moreover, 1-H indoline also failed to give any nitrated prod-
ucts. The above results clearly disclose the importance of the N centers of indolines

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D. LI ET AL.
Scheme 1. Gram-scale synthesis.
Scheme 2. Transformations of C5-nitrated indoline.
Scheme 3. Proposed reaction mechanism.
protecting with p-acceptors. Meanwhile, we also attempted several substrates that the C-
5 was substituted. Indolines bearing 5-Me or 5-Ph were applied as substrates in this
nitration reaction, giving the corresponding C7 products in moderate to good yields.
However, when indoline substituted with chloro group at C5 position, the C7 nitration
product could be afforded in 27% yield and a large amount of starting material was oxi-
dized. Meanwhile, when the indoline bearing the electron-donating C5-OMe group, we
could only get 18% yield of the target product and an unknown by-product.
Finally, the nitration reaction was examined in gram-scale as representative example
(Scheme 1). N-acetyl indoline (5.5 mmol) reacted with Fe(NO3)3ꢁ9H2O to afford 2a
0.83 g (80% yield) after 5 h, which suggests that the protocol is scalable.
Furthermore, to highlight the transformation of C-5 nitrated indolines, we performed
the oxidation of 2a using DDQ to give 5-nitrated indole 4a in 68% yield. In addition,
treatment of 2a with hydrochloric acid in a solution of ethanol refluxing for 4 h
afforded the free (NH)-indoline 3a in 94% yield (Scheme 2)
To gain more insights into the reaction mechanism, a free radical scavenger,
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, 1.0 equiv.), was added to the reaction
mixture, no desired target product could be observed under the standard reaction

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conditions, indicating that the reaction probably proceeded through a free rad-
ical process.
Based on above results and the previously reported reactions,[12] a plausible reaction
mechanism is proposed and shown in Scheme 3. First, Fe(NO3)3ꢁ9H2O generates the
NO2 radical under thermal conditions.[12] And then, the NO2 radical reacts with N-ace-
tyl indoline at the C-5 position to give the intermediate A which is further oxidized to
furnish B. Finally, the elimination of a proton from B would produce the desired prod-
uct. It should be noted that a mechanism involving the aromatic electrophilic substitu-
tion (EArS) pathway[14] could not be completely excluded.
Conclusion
In conclusion, we have demonstrated the regioselective C5 nitration of the N-pro-
tected indolines. This protocol only uses ferric nitrate as the nitrating reagent. The
reaction can be applied to a wide range of indolines smoothly in moderate to excel-
lent yields under mild conditions. In addition, the synthesized nitration products can
be further transformed to 5-nitroindolines and 5-nitroindole derivatives. The method
is operationally simple, efficient, and might have potential application in indus-
try production.
Experimental
Unless otherwise noted, all commercial materials and solvents were used without further
purification. Thin-layer chromatography (TLC) was carried out using silica-gel GF254
plates. Products were purified using column chromatography over 300–400 mesh silica
1
gel under a positive pressure of air. H NMR and 13C NMR spectra were referenced to
TMS and residue CHCl3 at 0.00 ppm and 77.16 ppm, respectively. High-resolution mass
spectra (HRMS) were measured with ESI-Orbitrap in positive mode.
General procedure (taking the synthesis of 2a as an example)
N-acetylindoline 1a (0.3 mmol), Fe(NO3)3ꢁ9H2O (60.5 mg, 0.15 mmol), in CH3CN (3 mL
or 6 mL) were added to a 25 mL oven-dried Schlenk tube equipped with a magnetic
stirred bar. The reaction was then stirred at 40 ꢂC without charging with inert gas. The
reaction was monitored using TLC and stopped at the desired time. Then, the solvent
was evaporated to dryness in vacuo. The residual was separated on a silica gel column
with petroleum ether and ethyl acetate as the eluent to give desired product 2a as a
brown yellow solid (55.3 mg, 89% yield): 1H NMR (400 MHz, CDCl3): d 8.29
(d, J ¼ 9.0 Hz, 1H), 8.12 (d, J ¼ 9.0 Hz, 1H), 8.04 (s, 1H), 4.20 (t, J ¼ 8.6 Hz, 2H), 3.30
(t, J ¼ 8.7 Hz, 2H), 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3): d 169.67, 148.43, 143.65,
132.47, 124.83, 120.40, 116.29, 49.56, 27.48, 24.42. HRMS (ESI-Orbitrap): m/z
[M þ Na]þ calcd for C10H10N2O3Na 229.0584, found 229.0581.

8
D. LI ET AL.
Funding
This work was supported by the key project of education department of Henan Province [Nos.
17A150050] and the Scientific and Technological Projects of Henan Province [Nos.
182102310066].
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