Using weak interactions to control C-H mono-nitration of indolines

Article abstract of DOI:10.1039/c7cc06267b

An unprecedented C-H mononitration of indolines either at the -C₅ or -C₇ positions under mild condition is reported here. The roles of multiple weak interactions and factors such as steric factors, electronic effects, cation-π interactions, and solvent polarity were established, and we achieved a 100% regioselective electrophilic aromatic (EArS) nitration using Cu(NO₃)₂ or AgNO₃.

Full text of DOI:10.1039/c7cc06267b

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Weak Interactions Controlled C-H Mono-Nitration of Indolines
Anima Bosea and Prasenjit Mala*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Under mild condition an unprecedented C-H mononitration of acids, carboxylic acids,18 aryl halides, aryl triflates, etc.19
A
indolines either at -C5 or -C7 positions is reported here. The role of reported example by Maiti and co-workers is shown in Fig. 1c
multiple weak interactions such as steric factors, electronic for the ipso-nitration on aryl boronic acids.17b
effects, cation-π interaction, solvent polarity, etc. was established
for the 100% regioselective electrophilic aromatic (ArSE) nitration
using Cu(NO3)2 or AgNO3.
Nitroarenes are important synthetic precursors in various
industries like agrochemical, pesticides, pharmacology, dyes,
polymers, etc. and preparations of those molecules are the
most extensively studied chemical reactions.1 High synthetic
utility of the nitroaryl moieties is due to their abundance and
easy synthetic transformation to other functional groups like
amino, diazo, etc.1-2 Few of the nitro substituted indoles have
potent activity towards tuberculosis.3
Regioselective nitration reactions of pharmaceutically
important indolines are desirable but challenging due to
unavailability of suitable methods.4 The aromatic electrophilic
nitration reactions (ArSE) are generally performed under harsh
conditions5 using the reagents like conc. HNO3-H2SO4,6
nitronium tetrafluoroborate,7 conc. HNO3-mixed anhydrides,8
N-nitropyridinium salts, NaNO3-TFA,9 etc.10 Therefore, ArSE
reactions may cause non-selective nitration of starting
materials4a or over oxidation on the products. Also, under
Fig. 1 The C-H mono-nitration. a) Our mono-nitration approach on the non-
prefunctionalized system under mild condition with 100% selectivity. b) Zhang’s
Ru- templated meta-selective C-H nitration via ortho-metalation template
strategy.16 c) Maiti’s ipso-nitration on aryl boronic acids.17b
highly acidic condition some functional groups like -CN, -CHO
Reactivity of chemical systems is known to be altered by
might get affected to make isolation procedure tedious.11
environment.20 The soft force21 of several low‐energy and
However, selective ArSE C-H nitrations are done via transition
low‐level multiple cooperative non-covalent or weak
metal-templated strategies.12 For example, commonly used
interactions22 like hydrophobic effect,23 anion-π,24 cation-π,25
transition metals in the C-H nitrations13 are Fe,14 Pd,15 Rh, Ru,16
etc. Zhang and co-workers have developed first meta-selective
Ru- catalysed C-H nitration via ortho-metalation template
etc. are considerably being explored in chemical systems.26 By
exploiting the weak interactions, the -C7 or -C5 selective ArSE
C-H mono-nitration of indolines (Fig. 1a) is demonstrated here
strategy (Fig. 1b).16 Also, using organometallic reagents,17 the
with an easy, convenient and mild27 approach. The mechanism
ipso-nitration are reported for the systems like aryl boronic
of the highly selective mono-nitration reaction is explained by
the use of non-covalent interactions and that can be
correlated to the concept of supramolecular catalysis.28
a.School of Chemical Sciences, National Institute of Science Education and
After screening several conditions using the unsubstituted
Research (NISER), HBNI, Bhubaneswar, PO Bhimpur-Padanpur, Via Jatni, District
N-acetyl indoline (1a) as the model substrate, the standard
condition of this nitration reaction was optimised (Table 1,
entry 11, 13). The best yield (up to 82%) of 5-nitro-1-acetyl
Khurda, Odisha 752050, India, E-mail. pmal@niser.ac.in
b.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of synthesis,
characterization and spectra]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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indoline (2a) was obtained using Cu(NO3)2.3H2O (1.1 equiv) or
AgNO3 (1.5 equiv) as -NO2 (nitro) source, potassium persulfate
(K2S2O8, 1.5 equiv) as oxidant and trifluoroacetic acid (TFA, 20
mol %), in 1,2-dichloroethane (DCE) at 80 ºC. Among the
solvents examined, acetonitrile, DMSO, DMF, 1,4-dioxane,
ethyl acetate, dichloromethane (entries 1-6) etc. were
completely ineffective for the transformation. In TFE, 68%
(entry 7) of 2a was isolated after 2.5 h, however, no product
could be detected in toluene (entry 8). Following, we have also
screened several nitrating agents and no products could be
isolated with KNO3 (entry 16) and NaNO3 (entry 17). The 2a
was obtained in 23% and 54%, using Bi(NO3)3 (entry 18) and
Fe(NO3)3 (entry 23), respectively. Moreover, using Ni(NO3)2
and Zn(NO3)2 the yield of 2a was obtained in 42% (entry 24)
and 39% (entry 25), respectively. Oxidants oxone or
phenyliodine diacetate (PIDA) (entry 19-21) were proved to be
less efficient compared to K2S2O8. However, under oxygen
atmosphere 48% of 2a was isolated after 24 h (entry 22). A
representational example is shown in entry 9 (Table 1) that
varying temperatures than 80 ºC did not have any positive
impact in the improvement of yields.
View Article Online
DOI: 10.1039/C7CC06267B
Fig. 2 Control Experiments.
Table 1. Optimization Method
entry
-NO2 source (equiv)
oxidant
(equiv)
K2S2O8 (3.0)
K2S2O8 (3.0)
Solvent, ºC
2a
(%)
--b
--
--
--
--
--
68
--
58
73
82
45
80
18
1a
2
3
4
5
6
7
8
9
10
11c
12
13c
14d
Cu(NO3)2 (1.0)
Cu(NO3)2 (1.0)
Cu(NO3)2 (1.2)
Cu(NO3)2 (1.2)
Cu(NO3)2 (1.2)
Cu(NO3)2 (1.2)
Cu(NO3)2 (1.2)
Cu(NO3)2 (1.2)
Cu(NO3)2 (1.0)
Cu(NO3)2 (1.0)
Cu(NO3)2 (1.1)
AgNO3 (1.0)
AgNO3 (1.5)
AgNO3 (0.2), KNO3
(2.0)
AgNO3 (0.2), NaNO3
(2.0)
ACN, 90
DMSO, 110
K2S2O8 (3.0) Dioxane, 90
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
DMF, 90
EtOAc, 90
DCM, 50
TFE, 80
Fig. 3 The non-covalent interactions in the nitration reaction.
To understand the mechanism of the reaction several control
experiments were performed. Using 1.0 equiv of 2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO), 2a was isolated in
64% yield (Fig. 2a) and that ruled out the possibility of the
nitration reaction via radical pathway. Under standard
condition D2O was added in the reaction mixture (Fig. 2b) to
confirm that any metal templated C-H activation mechanism
was not operating. The 1-methyl indoline and 1-H indoline
failed to give any nitrated products (Fig. 2c,d) and thus the
presence of carbonyl group was proved to be essential.
K2S2O8 (3.0) Toluene, 80
K2S2O8 (3.0)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (3.0)
K2S2O8 (1.5)
K2S2O8 (3.0)
DCE, 90
DCE, 80
DCE, 80
DCE, 80
DCE, 80
DCE, 80
15d
K2S2O8 (3.0)
DCE, 80
<10
The mechanism of selective mono-nitration of indoline
derivatives was proposed to be an aromatic electrophilic
substitution reaction (ArSE). The nitronium ion (+NO2) was
generated from Cu(NO3)2/AgNO3 in non-polar solvent DCE in
the presence of TFA (catalyst) and K2S2O8 (oxidant). For ArSE,
the C5- or C7- positions of the indolines were expected to be
sufficiently electron rich due to +R effect by nitrogen (Fig. 3b).
Therefore to avoid protonation under protic-environment and
simultaneous activation of the aromatic rings, N-centre of
indolines were protected with π-acceptors like -SO2 (tosyl,
mesyl) or -C=O (acetyl, pivaloyl, benzoyl) group (Fig. 3e). So, 1-
methyl indoline and 1-H indoline failed to give any product and
led to a very complex reaction mixture might be due to
16
17
18d
19d
20d
21
22 e
23 f
24f
25f
KNO3 (2.0)
NaNO3 (2.0)
Bi(NO3)3.5H2O
Cu(NO3)2 (1.2)
AgNO3 (1.5)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
Oxone(3.0)
Oxone(3.0)
PIDA (2.0)
O2
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
DCE, 80
DCE, 80
DCE, 80
DCE, 80
DCE, 80
DCE, 80
DCE, 80
DCE, 80
DCE, 80
DCE, 80
--
--
23
42
30
28
48
54
42
39
Cu(NO3)2 (1.2)
Cu(NO3)2 (1.1)
Fe(NO3)3.9H2O
Ni(NO3)2. 6H2O (1.2)
Zn(NO3)2. 6H2O (1.2)
aCu(NO3)2 used as Cu(NO3)2.3H2O, bNo reaction, TFA 20 mol %. Continued
for 16 h instead of 2 h. e24 h. f8 h.
c
d
2 | J. Name., 2012, 00, 1-3
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protonation (Fig. 2c,d). Amongst the metal ions and solvents worked efficiently (2l). Furthermore, N-methylacetanilide did
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examined (Table 1), the Cu2+/Ag+ ions in non-polar solvent DCE not results in any products even after 24DhO. I: 10.1039/C7CC06267B
led to the best results. The influence of cation-π interaction for
activation at C5- or C7- by Cu2+ or Ag+ ions (Fig. 2b) was
anticipated in the nitration reaction. Due to soft acid - soft
base nature (HSAB approach),29 Cu2+/Ag+ - aryl ring interaction
was preferred over K+/Na+ (hard acid) - aryl ring (soft base) via
cation-π activation. Obtaining 23% of the C5-H nitrated product
in presence of Bi(NO3)3.5H2O was also an indication for inferior
activation of aromatic ring by a relatively harder acid (Bi3+)
than Cu2+/Ag+. In high polar solvents (ACN, DMF, DMSO, etc.)
no products could be detected might be due to the absence of
weak cation-π interaction. The formation of C5-H nitration was
observed over C7-H nitration possibly because of the steric
effect of N-acetyl group (Fig. 3c). Therefore, C5-substituted
indolines led to C7-H nitration preferentially (vide infra). In one
pot the di-nitration reaction was unsuccessful even in
presence of excess nitrate salts (3.0 equiv) and TFA (1.0 equiv).
Fig. 5 Scope of C7-Nitration of Indolines.
Fig. 4 Scope of C5-Nitration of Indolines.
The substrates scope of the C-H mono-nitration protocol was
explored (Fig. 4). Compounds with substitution in the
pyrrolidine ring of indolines underwent smooth reaction to
give C5-nitrated products in good yields (Fig. 4). C2-Aryl
substituted indolines (2f, 2g) also resulted in the desired
products in 58% to 70% yield. C5-H nitrated products with
other N-protected indolines like N-pivaloyl (2e, 2f, 2g, 2h), N-
mesyl (2d) N-tosyl (2i) and N-benzoyl (2j) were also obtained in
58 to 72% as single regioisomer within 3 h.
Fig.
6 Synthetic Utility. a) Gram scale synthesis of 2a. b) Oxidation of
nitroindoline to nitroindole. c) Reduction of nitro-indoline to amino-indoline. d)
Acetyl group deprotection. e) Nitration of tetrahdroquinoline derivatives.
Towards synthetic utility, the compound 1a was converted to
2a in gram scale (ca. 1 gm) with 74% yield (Fig. 6a). The 5-
nitroindoline 2a was oxidised with DDQ and converted to 5-
nitroindole (3a) in 70% yield (Fig. 6b). The nitro group of 2a
was reduced to the corresponding amine with Fe (powder)-HCl
to obtain 3b in 80% yield (Fig. 6c). Deprotection of the acetyl
group with 10 M HCl led to 5-nitroindoline 3c (82% yield) (Fig.
6d). This methodology was also effective for the nitration of
C7-H nitrated products were obtained as the sole
regioisomeric products on C5-substituted indolines (Fig. 5).
Interestingly, C5-nitro indoline led to C5,C7-dinitro
(2k)
derivative in 60% yield at slightly longer time (4 h). The aryl
groups at the C5- position remain unaffected during the
nitration reaction (2p, 2q, 2r, 2s). Halogenated indolines also
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tetrahydroquinoline derivative (4, Fig. 6e) to 6-nitro-N-acyl-
tetrahydroquinoline (5) with 85% and 73% yields from the
methods A and B, respectively.
View Article Online
Res. Dev., 2017, 21, 125.
DOI: 10.1039/C7CC06267B
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In summary, the class of reactions and their suggested
mechanism prescribe
a
systematic pathway towards
programmable functional molecules using non-covalent
interactions. Strategically it is shown that by choosing
appropriate reaction condition difficult transformation can
also be done easily. Herein, we have demonstrated a method
for regioselective C5-H or C7-H mono-nitration of indolines. In
general, these results may also add a new aspect towards
development of supramolecular catalysis in organic chemistry.
The synthetic utility of the nitro-indolines towards synthesis of
various synthetic precursors are also documented. We foresee
that this mild and selective efficient nitration methodology can
offer direct access to the heterocyclic compounds and might
have a major impact on synthesis of functionalized materials,
complex molecules and pharmaceuticals.
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Acknowledgement
“We thank DST (New Delhi, India) for support and A.B. thank
CSIR (India) for fellowship
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Conflicts of interest
“There are no conflicts to declare”
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DOI: 10.1039/C7CC06267B
Weak Interactions Controlled C-H Mono-Nitration of Indolines
By utilising simultaneous cooperative multiple weak interactions (soft force), mild and
selective C5-H or C7-H mono-nitration of indoline is demonstrated.