Copper-Catalyzed Chelation-Assisted ortho-Nitration of 2-Aryls Using Pharmacophoric Benzothiazoles and Benzoxazoles as Directing Groups

Article abstract of DOI:10.1002/ejoc.201701187

A copper-catalyzed chelation-assisted ortho-nitration reaction of aryl derivtives has been achieved, using benzazoles as efficient directing groups. The reaction is general and efficient for aryl derivatives with various electronic properties, and also with different pharmacophorically important directing groups, i.e., benzoxazoles, benzothiazoles, and benzimidazoles. The nitro-group-containing products have significance as fluorogenic compounds and potential nitroreductase substrates that could be used for the detection of clinically important microorganisms. The nitration reaction proceeds with an inexpensive copper catalyst and a mild, cheap, and environmentally friendly nitro source, Fe(NO₃)₃·9H₂O. This operationally simple and functional-group-tolerant protocol for the nitration of 2-aryl benzazoles proceeds with a high regioselectivity without the exclusion of air or moisture.

Full text of DOI:10.1002/ejoc.201701187

A Journal of
Accepted Article
Title: Copper-Catalyzed Chelation Assisted ortho-Nitration of 2-Aryls
with Pharmacophoric Benzo-thiazoles and -oxazoles as Directing
Groups.
Authors: Chandrasekharam Malapaka, vinayak botla, and Ashok
Akudari
This manuscript has been accepted after peer review and appears as an
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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
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701187
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701187
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10.1002/ejoc.201701187
European Journal of Organic Chemistry
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Copper-Catalyzed Chelation Assisted ortho-Nitration of 2-Aryls
with Pharmacophoric Benzo-thiazoles and -oxazoles as Directing
Groups.
Botla Vinayak,‡ Akudari Ashok‡ and Malapaka Chandrasekharam*
Abstract: Copper-catalyzed chelation assisted ortho-nitration of
aryls with benzazoles as efficient directing group has been achieved.
The reaction is general and efficient for electronically differentiated
aryls and pharmacophorically important directing groups i.e.,
benzoxazoles, benzthiazoles and benzimidazoles. This class of
nitro-products have significance as fluorogenic and potential
nitroreductase substrates for the detection of clinically important
microorganisms. The nitration reaction proceeds with inexpensive
copper catalyst and mild, cheap and environmentally friendly nitro
source, Fe(NO3)3.9H2O. This operationally simple and functional
group tolerant protocol highlights the high regioselectivity for the
nitration of 2-aryl benzazoles without the exclusion of air or moisture.
warrant removal at the end.[6]
On the other hand Benzazole scaffolds are found in natural
products, pharmaceuticals and agrochemicals.[7] Particularly aryl
benzazoles are important pharmacophores with biological
activities, such as anti-HIV, antibiotic, anti-microbial, anti-
inflammatory and anti-tumor properties.[8] Further detection,
enumeration and identification of harmful bacteria are connected
to our day to day life particularly in the basic areas of health,
food and environment.[9] In this context 2-(2’-nitro)aryl-benzo-
thiazole and -oxazole derivatives are known to be fluorogenic
and potential nitroreductase substrates for the detection of
clinically important microorganisms[10] and hence synthesis and
biological study of these compounds attracted increased
attention. In addition to the biological significance, benzazoles
are versatile biorelevant heterocyclic DGs. Although N- donor
atom as the DG has been widely employed in direct o-arylation,
Introduction
Introduction of nitrogen atoms into organic molecules is the
subject of intense interest. Nitroarenes are versatile aromatic
building blocks in organic synthesis due to their wide usage as
chemical feedstock in industry, for the synthesis of drugs, dyes,
perfumes, fertilizers, plastics and explosives.[1] Nitroarenes not
only serve as versatile substrates for sulfonamidation and
Barans hydroamination but also are excellent electrophilic
coupling partners in Suzuki-Miyaura coupling reactions to
access a wide range of functionalized biaryls.[2] Classical
methods of nitroarene synthesis involve Friedel-Crafts type
nitration to obtain predominantly the para-nitro compounds.
These reactions suffer from the use of strong acids, intolerance
of diverse functional groups, and low ortho/meta site-selectivitiy.
-acetoxylation,
-alkylation, -alkenylation,
-fluorination
-
hydroxylation and recently o-nitration, most of these
transformations required precious Rh and Pd metal
catalysts.[11,12] Further less expensive and environmentally
benign methods surrogates the traditional use of expensive and
noble transition metals such as rhodium, ruthenium, palladium
etc.[13a] Despite of the above, forging of the Nitro group, an
important functionality at the ortho- position on 2-aryl benzazoles
has not been adequately addressed in the chemical literature.
Recently Leng & Wu group reported chelation assisted ortho-
nitration employing precious Pd metal and AgNO2 under difficult
to operate, external oxygen and energy intensive, drastic
reaction conditions with the substrate scope limited to 2-
arylbenzoxazoles.[12j] Therefore we assumed that the
developement of a general reaction protocol for the ortho-
nitration of 2-aryl benzo-oxazole and -thiazole scaffolds with less
expensive and earth abundant catalyst, under easy to operate
reaction conditions is warranted.
[3]
The direct transformation of C-H bonds to C-C and C-X
(heteroatom) offers easy access to many natural and synthetic
complex molecules. Particularly directing group (DG) assisted
reactions forge new bonds selectively at one C-H bond in a
molecule among several other reactive C-H bonds in a single
step overriding the innate reactivity of the substrate and
eliminating the additional prefunctionalization step.[4] In recent
times,
transition
metal-catalyzed
DG-assisted
C-H
Scheme 1. Ortho-Nitration of 2-aryl Benzazole.
functionalizations received increased attention as powerful C-C,
C-N, and C-O bond-forming reactions and in this context
regioselective aryl nitration is an important transformation.[5]
Further traceless, easily removable and transient DG-assisted
C-H functionalizations are gaining tremendous importance in
order to prevent additional steps in the reaction sequence.
However pharmacophorically significant DGs, provide value
addition to the product and therefore does not necessarily
.
In our laboratory we have been engaged in the transitional metal
mediated C-H functionalization (C-C, C-O and C-N) and
condensation reactions with particular emphasis on green
technologies.[13] Further we recently reported two efficient
regioselective aryl nitration protocols involving 1. Concomitant
azidation-oxidation chemistry with TMS azide, TBHP and copper
catalyst [13g] 2. Fe(NO3)3.9H2O with dual role as catalyst and nitro
source.[13a] Both of these strategies are effective under aerobic
conditions. Our above studies on aryl nitration combined with the
Botla Vinayak, Akudari Ashok and Malapaka Chandrasekharam
Inorganic & Physical Chemistry Division,
CSIR- Indian Institute of Chemical Technology,
Uppal Road, Tarnaka, Hyderabad-500007, India
E-mail: chandra@iict.res.in
‡
These authors equally contributed.
Supporting information for this article is given via a link at the end of the
document.
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10.1002/ejoc.201701187
European Journal of Organic Chemistry
FULL PAPER
biological importance of 2-(2’-nitro)aryl benzazoles prompted us
to investigate further on DG-assisted aryl nitrations and we
herein, report our new findings wherein copper-catalyzed
chelation assisted ortho-nitration on aryls is effected with
biorelevant 2-aryl-benzthiazoles and -benzoxazoles as DGs that
proceed without the exclusion of air or moisture.
[a] The Reaction was performed with 1b (1.0 mmol), catalyst (20 mmol %),
nitro source (2.0 mmol), oxidant (2.0 mmol) in 1,2 DCE solvent, reflux 24 h in
an open air atmosphere unless otherwise noted. [b] Isolated yields, [c] catalyst
(10 mmol %), [d] catalyst (40 mmol %), [e] under Oxygen atmosphere [f]
Nitrogen atmosphere, [g] 4 Å molecular sieves.
We initiated our investigation with 2-(p-tolyl)benzo[d]thiazole 1b
as a model substrate to examine various nitrating agents,
solvents and catalysts for the optimization of reaction conditions
(Table 1). The nitration reaction conducted at room temperature
with CuCl2 (20 mol %) and Fe(NO3)3·9H2O (1.0 equiv) in DCE for
24 h produced no desired product, However the reaction
conducted with CuCl2 (20 mol %) and Fe(NO3)3·9H2O (2.0 equiv)
at reflux (83 °C) resulted in poor yields (28%) of the product (2b)
and significant quantity of starting material (1b) was recovered.
To examine the advantage of additive, the nitration reaction was
carried out in presence of DTBP (2.0 equiv) and found that the
yield of nitro product 2b was increased to 42% (Entry 3, Table 1).
Among various other additives (Benzoyl peroxide, K2S2O8 and
Ag2O) tested Ag2O proved to be the most efficient affording 83%
Results and Discussion
Table 1. Optimization of Ortho-Nitration of 2-aryl bezothiazoles.[a]
S.No
Catalyst
Nitro source(equiv)
Additive
Yield
(%)[b]
1
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuBr2
Fe(NO3)3·9H2O(1.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Cu(NO3)2·3H2O(2.0)
AgNO3(2.0)
-
-
Scheme 2. Substrate Scope of Ortho-Nitration of 2-aryl benzazoles. [a]
2
-
28
42
51
69
83
21
-
3
DTBP
BP
4
5
K2S2O8
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
6
7
8
9
AgNO2(2.0)
-
10
11
12
13
14
15
Bi(NO3)3·5H2O(2.0)
Co(NO3)3.6H2O(2.0)
NaNO2(2.0)
-
-
-
KNO2(2.0)
-
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
34
42
Cu(OAc)2·
H2O
16
CuI
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Fe(NO3)3·9H2O(2.0)
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
35
-
17
FeCl3
FeBr3
Pd(OAc)2
CuCl2.2H2O
-
18
-
19
13
72
-
[a] The Reaction was performed with 1 (1.0 mmol), CuCl2 (20 mmol %),
Fe(NO3)3.9H2O (2.0 mmol), Ag2O (2.0 mmol) in 1,2 DCE solvent, reflux 24 h in
an open air atmosphere unless otherwise noted. [b] Isolated yields.
20
21
yield of the product (Entries 4-6, Table 1). Fe(NO3)2·9H2O was
found to be the most effective nitro source (Entry 6, Table 1),
while other nitrating agents including Cu(NO3)2.3H2O are
deleterious for this reaction (Entries 7-13, Table 1). Other
transition metal catalysts i.e., iron, palladium salts were tested
(Entries 14-20, Table 1) and in the absence of catalyst, the
reaction did not proceed (Entry 21, Table 1). The copper
chloride is found to be the most suitable and efficient catalyst for
22c
23d
24e
25f
26g
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
71
71
69
74
71
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10.1002/ejoc.201701187
European Journal of Organic Chemistry
FULL PAPER
this chelation assisted ortho-nitration. Further 10 mol% of
catalyst loading decreased the product yield dramatically, while
increasing to 40 mol% did not significantly change the outcome
of the reaction (Entries 22, 23, Table 1). The reaction outcome
was not significantly changed in the presence of oxygen or
nitrogen atmosphere (Entry 24, 25, Table 1). Neither the product
yield improved when reaction was conducted in the presence of
additive, 4 Å molecular sieves. (Entry 26, Table 1), with the
optimized conditions in hand, the scope of the reaction was
investigated with various electronically differentiated substrates
(Table 2). Good yields were often achieved when electron-
donating moieties including 4-methyl, 4-ethyl, 4-tert-butyl, 4-
methoxy and 4-allyloxy groups were present on the phenyl ring
of 2-arylbenzothiazoles under the standard reaction conditions
(Table 2, 2b–2f). 3,4,5-Trimethoxy phenyl substituted
benzthiazole also found to be a good substrate for this nitration
reaction producing 74% yield of the product. (Table 2, 2g)
Moderate to good yields of the corresponding products were
obtained with 4-fluoro, 4-chloro, 3-chloro, 4-bromo and 4-
trifluoromethyl phenyl benzothiazole. (Table 2, 2h-2l). Then the
substrate scope was expanded to 2-aryl benzoxazoles where
benzoxazole serving as DG. The unsubstituted substrate as well
as the substrates with e-donating alkyl/alkoxy substitutions on
either of the aryl rings of the benzoxazoles are effective for this
chelation assisted nitration reaction (Table 2, 2m-2r). 3-chloro
and 4-bromo phenyl benzoxazoles also underwent nitration
affording the corresponding products in 62% and 59% yields
respectively under the optimized reaction conditions. (Table 2,
2s-2t). These halogen subistitutions on the aryl ring would allow
further decoration of the nitro benzazoles to produce value
added products.14 Moreover the ortho-nitration protocol is further
extended to the substrate 2-aryl- N-methyl benzimidazole and
produced product 2v in 63% yield demonstrating that
benzimidazole is also an effective DG for the nitration reaction.
All the new compounds have been fully characterized with 1H
and 13C NMR, Mass and HRMS.
chelation-assisted ortho-nitration of 2-aryl benzazoles (Scheme
4). Initially, copper chloride is coordinated with nitrogen of the 2-
aryl benzazole to give intermediate A. Subsequently the nitrate
ion-containing copper (II) complex B was formed by anion
exchange. We propose two pathways for the formation of ortho-
nitro product from complex B. The intermediate B undergoes a
single electron transfer (SET) event from the aryl ring to the
coordinated Cu(II) leading to the formation of a radical cation
intermediate C.
Scheme 4. Proposed Mechanism.
Subsequently the radical cation is trapped with the nitro group
present in the proximity forming the cationic species D. Finally
deprotonation of intermediate
D
generates the desired
product.[15b] Following path a, a four centered bridged transition
state is presumed to operate wherein cleavage of C-H and N-O
bonds and simultaneous formation of O-H and C-N bonds
occurred through a concerted mechanism delivering the ortho-
nitro product.[15a] Overall the regioselectivity of the chelation
assisted nitration is controlled by DG assisted proximity effect.
Scheme 3. Mechanistic Insights.
Conclusions
In conclusion we have achieved the copper-catalyzed chelation
assisted ortho-nitration of aryls with bio-relevant 2-aryl
benzazoles serving as efficient directing groups. The reaction
proceeds well with wide substrate scope (benzo-oxazoles, -
thiazoles and -imidazoles) and high functional group tolerance in
presence of iron(III) nitrate as a mild nitro source without the
exclusion of air or moisture. The halo appended nitro products
could be used as handles for further functional group
transformation. Employment of non toxic, inexpensive and
To understand the mechanism, 1b was subjected to the
standard reaction conditions in the presence of the radical
scavenger TEMPO, which led to a diminished yield (13%) of the
product 2b demonstrating that a radical species may be involved
in the reaction process. When 1,1-diphenylethylene was
employed as a radical acceptor, formation of neither 2b nor
radical intercepted product was detected. These experiments
demonstrate that the ortho-nitration reaction may proceed via a
radical mechanism.
readily available copper catalyst and
iron nitro source
combined with operational simplicity highlights the efficiency of
this reaction. Further mechanistic investigations and testing of
these nitro products as fluorogenic and potential nitroreductase
substrates for the detection of clinically important
microorganisms are underway in our laboratory.
Although the reaction mechanism is not clear yet, from the
above observations and prior literature,[15]
a
plausible
mechanism has been proposed for the copper-catalyzed
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10.1002/ejoc.201701187
European Journal of Organic Chemistry
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Experimental Section
3H), 13C NMR(100 MHz, CDCl3) 173.5, 162.7, 158.0, 144.5, 135.1, 129.6,
125.5, 122.7, 121.8, 118.0, 114.6, 55.5, ESI-MS: m/z 287 (M+H)+, HRMS
(ESI) m/z [M+H]+ calcd for C14H11O3N2S = 287.04849, found 287.04908.
General Considerations: All commercially available chemicals were used
as received. Thin-layer chromatography plates were visualized by
exposure to UV or Iodine, and/or by immersion in an acidic staining
solution of phosphomolybdic acid followed by heating on a hot plate. 1H
NMR spectra were obtained with 400 and 500 MHz spectrometers, 13C
NMR spectra were obtained with 100 and 125 MHz spectrometers in
CDCl3 at 298 K with tetramethylsilane and CDCl3 as the internal
standard. Chemical shifts (δ) are reported in ppm relative to the residual
solvent signal (δ = 7.26 ppm for 1H NMR and δ = 77.0 ppm for 13C
NMR). Data for 1H NMR are reported as follows: chemical shift
(multiplicity, coupling constant, number of hydrogen atoms). Multiplicity is
abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet). Mass spectra were carried out with a Quattro LC triple-
quadrupole mass spectrometer (Micromass, Manchester, UK). High-
resolution mass spectra were determined with a Quadrupole time-of-flight
(Q-TOF) mass spectrometer (QSTARXL, Applied Biosystems/MDS Sciex,
Foster city, USA).
2-(4-(allyloxy)-2-nitrophenyl)benzo[d]thiazole (2f); Pale yellow solid,
°
mp. 172-174 C, 1H NMR (400 MHz, CDCl3) δ: 8.93-8.72 (m, 1H), 8.41-
8.28 (m, 1H),8.19-7.95 (m, 3H), 7.14-6.99 (m, 2H), 6.18-5.97 (m, 1H),
5.51-5.39 (m, 1H), 5.38-5.28 (m, 1H), 4.72-4.56 (m, 2H). 13C NMR (100
MHz, CDCl3) δ: 173.4, 161.9, 158.0, 144.5, 133.0, 129.6, 125.5, 122.7,
121.8, 118.2, 118.0, 115.3, 68.9, ESI-MS: m/z 313 (M+H)+
2-(3,4,5-trimethoxy-2-nitrophenyl)benzo[d]thiazole (2g); Pale yellow
solid, mp. 110-112 °C, 1H NMR (500 MHz, CDCl3) δ: 8.07 (d, J = 8.24 Hz,
1H), 7.90 (d, J = 7.93 Hz,, 1H), 7.53-748 (m, 1H), 7.45-7.39 (m, 1H) 7.12-
7.10 (m, 1H), 4.034-4.02 (s, 3H), 4.00 (s, 3H), 3.98 (s, 3H), 13C NMR (100
MHz, CDCl3) δ: 161.1, 154.5, 153.3, 146.5, 144.3, 135.3, 126.5, 125.8,
124.0, 121.4, 108.0, 62.6, 61.2, 56.5; HRMS (ESI) m/z [M + H]+ calcd for
C16H15O5N2S = 347.06962 found 347.06949.
2-(4-fluoro-2-nitrophenyl)benzo[d]thiazole (2h); Pale yellow solid, mp.
90-92 °C, 1H NMR (400 MHz, CDCl3) δ: 8.09 (d, J = 8.31 Hz, 1H), 7.94 (d,
J = 7.45 Hz, 1H), 7.85-7.79 (m, 1H), 7.70-7.64 (m, 1H), 7.56-7.52 (m, 1H),
7.48-7.41 (m, 2H), 13C NMR (125 MHz, CDCl3) δ: 164.1, 161.5, 161.2,
153.4, 135.7, 133.5, 126.6, 125.9, 123.9, 121.5, 119.7, 119.5, 112.7,
117.4; ESI-MS: m/z 275 (M+H)+
General Procedure for ortho-Nitration of 2-aryl benzazoles:
A 10 mL round-bottomed flask was charged with 2-Aryl benzothiazole or
benzoxazole (1a-u) (1.0 mmol), were dissolved in 1, 2 DCE (3 mL) and
copper(II)chloride (20 mol %), Fe(NO3)3.9H2O (2.0 mmol) and Ag2O (2.0
mmol), were sequentially added and the reaction mixture was stirred at
reflux 83 °C and reaction progress was observed by TLC (24 h). After
completion of the reaction the crude compound obtained was washed
with a saturated aqueous solution of brine (aq NaCl) and then extracted
with ethyl acetate. The combined organic layers were dried with Na2SO4,
and the solvent was evaporated under reduced pressure. The crude
product was purified by column chromatography (60–120 mesh; hexane/
ethyl acetate) to obtain the desired product.
2-(4-chloro-2-nitrophenyl)benzo[d]thiazole (2i); Pale yellow solid, mp.
°
230-232 C, 1H NMR (500 MHz, CDCl3) δ: 8.88-8.84 (m, 1H), 8.41-8.36
(m, 1H), 8.16-8.12 (m, 1H), 8.09-8.06 (m, 2H), 13C NMR (125 MHz,
CDCl3) δ: 129.6, 129.0, 123.4, 122.0, 118.262; ESI-MS: m/z 291 (M+H)+.
2-(3-chloro-2-nitrophenyl)benzo[d]thiazole (2j); Pale yellow solid, mp.
°
225-227 C, 1H NMR (400 MHz ,CDCl3) δ: 8.13-8.07 (m, 1H), 7.98-7.90
(m, 2H), 7.80-7.79 (m, 1H), 7.63-7.60 (m, 1H), 7.57-7.45 (m, 2H), 13C
NMR (125 MHz, CDCl3) δ: 138.4, 131.2, 129.09, 123.4, 122.0, 118.262;
HRMS (ESI) m/z [M+.] calcd for C13H8O2N2ClS = 290.99895 found
290.99858.
Characterization Data
2-(2-nitrophenyl)benzo[d]thiazole (2a): [12j] Pale yellow solid, mp. 116-
118 °C, 1H NMR (400 MHz, CDCl3) δ: 8.12-8.08 (m, 2H), 7.92 (d, J = 8.15
Hz, 1H), 7.52-7.47 (m, 4H), 7.41-7.36 (m, 1H), 13CNMR (125 MHz,
CDCl3) δ: 168.0, 154.0, 135.0, 133.5, 130.9, 128.9, 127.5, 126.2, 125.1,
123.1, 121.5; ESI-MS: m/z 257 (M+H)+
2-(4-bromo-2-nitrophenyl)benzo[d]thiazole (2k); Pale yellow solid, mp.
110-112 °C, 1H NMR (400 MHz, CDCl3) δ: 8.13-8.01 (m, 2H), 7.95 (d, J =
7.82, 1H), 7.87-7.81 (m, 1H), 7.70 (d, J = 8.19, 1H), 7.56-7.51 (m,
1H),7.49-7.43 (m, 1H), 13C NMR (100 MHz, CDCl3) δ: 161.0, 153.5,
149.0, 135.7, 135.3, 132.8, 127.5, 126.7, 126.0, 124.5, 124.0, 121.5;
ESI-MS: m/z 335 (M)+. HRMS (ESI) m/z [M-H]+. calcd for C13H8O2N2BrS
= 334.94844 found 334.94829.
2-(4-methyl-2nitrophenyl)benzo[d]thiazole (2b); Pale yellow solid, mp.
°
86-88 C, 1HNMR (400 MHz, CDCl3) δ: 8.85-8.80 (m, 1H), 8.37-8.34 (m,
1H), 8.12-8.09 (m, J = 8.85 Hz, 1H), 8.03-7.99 (d, J = 8.19 Hz, 2H), 7.36-
7.32 (d, J = 8.06 Hz, 2H), 2.48 (m, 3H) 13C NMR (125 MHz, CDCl3),
173.9, 157.9, 144.7, 142.9, 135.1, 129.9, 127.8, 123.0, 121.8, 118.1,
21.6; ESI-MS: m/z 271 (M+H)+,
2-(2-nitro-4-(trifluoromethyl)phenyl)benzo[d]thiazole (2l); Pale yellow
°
solid, mp. 156-158 C, 1H NMR (500 MHz, CDCl3) δ: 8.43-8.38 (m, 1H),
8.26 (d, J = 8.08 Hz, 2H), 8.22-8.17 (m, 1H), 7.81 (d, J = 8.08 Hz, 2H),
13C NMR (100 MHz, CDCl3), 171.6, 157.5, 145.3, 135.7, 135.4, 128.2,
126.2, 123.8, 122.1,118.3; ESI-MS: m/z 325 (M+H)+,
2-(4-ethyl-2-nitrophenyl)benzo[d]thiazole (2c): Pale yellow solid, mp.
164-166 °C, 1H NMR (400 MHz, CDCl3) δ: 8.82 (d, J = 2.20 Hz, 1H),
8.378.34 (m, 1H), 8.12-8.10 (m, 1H), 8.04 (d, J = 8.34 Hz, 2H), 7.36 (d, J
= 8.34 Hz, 2H), 2.78-2.71 (m, 2H), 1.32-1.27 (m, 3H), 13CNMR (100 MHz,
CDCl3) δ: 173.9, 157.9, 149.2, 144.7, 135.1, 130.2, 128.7, 127.9, 123.0,
121.8, 118.1, 28.9, 15.1, ESI-MS: m/z 285 (M+H)+
2-(2-nitrophenyl)benzo[d]oxazole (2m):[12j] Yellow solid, mp.104-106 °C
1H NMR (400 MHz, CDCl3) δ: 8.17-8.14 (m, 1H), 7.91 (d, J = 7.51 Hz,
1H), 7.83-7.81 (m, 1H), 7.78-7.63 (m, 2H), 7.59-7.57 (m, 1H), 7.43-7.38
(m, 2H). 13C NMR (100 MHz, CDCl3) δ 158.80, 151.00, 149.18, 141.52,
132.37, 131.86, 131.41, 126.05, 124.95, 124.22, 121.48, 120.70, 110.94.
2-(4-(tert-butyl)-2-nitrophenyl)benzo[d]thiazole (2d); Pale yellow solid,
°
mp. 144-146 C, 1H NMR (400 MHz, CDCl3) δ: 8.84-8.82 (m, 1H), 8.38-
8.35 (m, 1H), 8.12 (d, J = 8.92 1H), 8.06 (d, J = 8.31 2H), 7.56 (d, J =
8.43 2H), 1.59-1.53 (s, 9H), 13C NMR (100 MHz, CDCl3) δ: 157.9, 156.0,
135.2, 130.0, 127.7, 126.1, 123.1, 121.8, 118.1, 31.1, 29.6; ESI-MS: m/z
313 (M+H)+, HRMS (ESI) m/z [M+H]+ calcd for C17H17O2N2S = 313.10053
found 313.10047.
5-methyl-2-(2-nitrophenyl)benzo[d]oxazole (2n): [16a] Pale yellow solid,
°
mp. 134-136 C, 1H NMR (400 MHz, CDCl3) δ: 8.32-8.23 (m, 3H), 7.70-
7.65 (m, 1H), 7.63-7.54 (m, 3H), 2.74 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 166.2, 154.2, 145.3, 143.4,129.8, 128.0, 123.1, 120.9, 116.0,
110.5, 21.7; ESI-MS: m/z 255 (M+H)+, HRMS (ESI) m/z [M+H]+ calcd for
C14H11 O3N2 = 255.07642 found 255.07608.
2-(4-methoxy-2-nitrophenyl)benzo[d]thiazole (2e): Pale yellow solid,
mp. 178-180 °C, 1HNMR (500 MHz, CDCl3) δ: 8.80 (d, J = 2.28 Hz, 1H),
8.36-8.33 (m, 1H), 8.08-8.05 (m, 3H), 7.03 (d, J = 9.00 Hz, 2H), 3.91 (s,
6-methyl-2-(2-nitrophenyl)benzo[d]oxazole (2o): [16b] Pale yellow solid,
mp. 103-105 °C, 1H NMR (400 MHz, CDCl3) δ: 8.40 (s, 1H), 8.26-8.22 (m,
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10.1002/ejoc.201701187
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2H), 7.60-7.50 (m, 4H), 2.74 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 165.3,
152.9, 146.7, 132.3, 131.6, 129.0, 127.9, 126.150, 116.9, 113.4, 21.3;
ESI-MS: m/z 255 (M+H)+ HRMS (ESI) m/z [M+H]+ calcd for C14H11O3N2 =
255.07642 found 255.07606.
Int. Ed. 2014, 53, 13808; d) H. Gao, D. H. Ess, M. Yousufuddin, L.
Kꢀrti, J. Am. Chem. Soc. 2013, 135, 7086; e) M. R. Yadav, M. Nagaoka,
M. Kashihara, R.-L. Zhong, T. Miyazaki, S. Sakaki, Y. Nakao, J. Am.
Chem. Soc 2017, 139, 9423.
[3]
[4]
a) K. Niknam, M. A. Zolfigol, E. Madrakian, E. Ghaemi, South African J.
Chem. 2007, 60, 109; b) S. Sana, K. C. Rajanna, K. R. Reddy, M.
Bhooshan, M. Venkateswarlu, M. S. Kumar, K. Uppalaiah, Green
Sustain. Chem. 2012, 2, 97; c) Abdulla, S. Amina, Y. A. Kumar, M.
Arifuddin, K. C. Rajanna, Synth. Commun. 2011, 41, 2946; d) Z. Fan, J.
Ni, A. Zhang, J. Am. Chem. Soc 2016, 138, 8470–8475.
2-(2-methyl-6-nitrophenyl)benzo[d]oxazole (2p): [12j] Yellow solid, mp.
°
59-61 C, 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.51 Hz, 1H), 7.84-
7.81 (m, 1H), 7.64-7.60 (m, 3H), 7.42-7.40 (m, 2H), 2.43 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 158.6, 150.8, 149.5, 141.5, 141.4, 135.4,
131.0, 125.6, 124.7, 122.9, 122.3, 120.5, 110.9, 20.0.
a) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang, Org. Chem.
Front. 2015, 2, 1107; b) L. Yang, H. Huang, Chem. Rev. 2015, 115,
3468–3517; c) X. Wu, Chem. Eur. J. 2015, 21, 12252; d) R. K. Rit, M. R.
Yadav, K. Ghosh, A. K. Sahoo, Tetrahedron 2015, 71, 4450; e) M.
Zhang, Y. Zhang, X. Jie, H. Zhao, G. Li, W. Su, Org. Chem. Front. 2014,
1, 843; f) C. Zhao, M. R. Crimmin, F. D. Toste, R. G. Bergman, Acc.
Chem. Res. 2013, 47, 517; g) L. Ackermann, Acc. Chem. Res. 2013,
47, 281; h) L. C. M. Castro, N. Chatani, Chem. Lett. 2015, 44, 410; i) K.
M. Engle, J.-Q. Yu, J. Org. Chem. 2013, 78, 8927; j) S. R. Neufeldt, M.
S. Sanford, Acc. Chem. Res. 2012, 45, 936; k) D. Zhao, J. You, C. Hu,
Chem. Eur. J. 2011, 17, 5466; l) P. B. Arockiam, C. Bruneau, P. H.
Dixneuf, Chem. Rev. 2012, 112, 5879; m) D. A. Colby, A. S. Tsai, R. G.
Bergman, J. A. Ellman, Acc. Chem. Res. 2011, 45, 814; n) S. R.
Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012, 45, 936; o) L.
Ackermann, Acc. Chem. Res. 2013, 47, 281; p) Z. Chen, B. Wang, J.
Zhang, W. Yu, Z. Liu, Y. Zhang, Org. Chem. Front. 2015, 2, 1107; q) R.
Sharma, K. Thakur, R. Kumar, I. Kumar, U. Sharma, Catal. Rev. 2015,
57, 345; r) J. Yang, Org. Biomol. Chem. 2015, 13, 1930.
6-methyl-2-(4-methyl-2-nitrophenyl)benzo[d]oxazole (2q); Pale yellow
°
solid, mp. 178-180 C 1H NMR (400 MHz, CDCl3) δ: 8.27 (s, 1H), 8.18-
8.13 (m, 2H), 7.62-7.50 (m, 4H). 13C NMR (100MHz, CDCl3) δ: 167.4,
148.1, 146.1, 145.7, 143.5, 131.1, 129.8, 128.1, 123.2, 122.4, 107.8,
21.7, 21.3; ESI-MS: m/z 269 (M+H)+, HRMS (ESI) m/z [M +H]+ calcd for
C15H13O3N2 = 269.09207 found 269.09161.
2-(4-methoxy-2-nitrophenyl)benzo[d]oxazole (2r): [12j] Yellow solid, mp.
110-112 °C, 1H NMR (400 MHz, CDCl3) δ: 8.07 (d, J = 8.84 Hz, 1H),
7.79- 7.77 (m, 1H), 7.56-7.53 (m, 1H), 7.38-7.34 (m, 3H), 7.21 (d, J =
8.81 Hz, 1H), 3.94 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 162.0, 158.9,
150.9, 150.3, 141.6, 132.5, 125.6, 124.7, 120.4, 117.8, 113.3, 110.7,
109.7, 56.2.
2-(3-chloro-2-nitrophenyl)-6-methylbenzo[d]oxazole (2s); Pale yellow
°
solid, mp. 150-152 C, 1H NMR (400 MHz, CDCl3) δ: 8.30-8.26 (m, 2H),
8.17-8.14 (m, 1H), 7.69 (s, 1H) 7.59-7.56 (m, 1H), 7.53-7.48 (m. 1H); 13
C
[5]
a) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 2009, 110,
624–655; (b) C.-L. Sun, B.-J. Li, Z.-J. Shi, Chem. Rev 2011, 111, 1293–
1314; (c) A. E. Wendlandt, A. M. Suess, S. S. Stahl, Angew. Chemie Int.
Ed. 2011, 50, 11062–11087; (d) M. C. White, Science (80-. ). 2012, 335,
807–809; (e) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem.
Res 2012, 45, 788–802; (f) A. J. Hickman, M. S. Sanford, Nature 2012,
484, 177; (g) C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41,
3464–3484; (h) L. D. Tran, J. Roane, O. Daugulis, Angew. Chemie Int.
Ed. 2013, 52, 6043–6046; (i) J. Pan, M. Su, S. L. Buchwald, Angew.
Chemie Int. Ed. 2011, 50, 8647–8651; (j) W. C. P. Tsang, N. Zheng, S.
L. Buchwald, J. Am. Chem. Soc. 2005, 127, 14560–14561; (k) J.
Wencel-Delord, T. Dröge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40,
4740–4761; (l) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215–
1292; (m) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111,
1780–1824; (n) S. H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem. Soc.
Rev. 2011, 40, 5068–5083; (o)T. W. Lyons, M. S. Sanford, Chem. Rev.
2010, 110, 1147–1169; (p)F. Bellina, R. Rossi, Chem. Rev. 2009, 110,
1082–1146; (q) N. Kuhl, M. N. Hopkinson, J. Wencel‐Delord, F. Glorius,
Angew. Chemie Int. Ed. 2012, 51, 10236–10254; (r) L. Ackermann,
Chem. Rev. 2011, 111, 1315–1345; (s) L. Chen, E. Shi, Z. Liu, S. Chen,
W. Wei, H. Li, K. Xu, X. Wan, Chem. Eur. J. 2011, 17, 4085–4089; (t) X.
Wang, Y. Lu, H.-X. Dai, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132,
12203–12205; (u) T. Naveen, S. Maity, U. Sharma, D. Maiti, J. Org.
Chem., 2013, 78, 5949; (v) S. Maity, S. Manna, S. Rana, T. Naveen, A.
Mallick, D. Maiti, J. Am. Chem. Soc., 2013, 135, 3355.
NMR (125 MHz, CDCl3) δ: 165.6, 148.2, 146.3, 145.6, 135.3, 132.6,
131.2, 130.4, 128.0, 127.7, 126.1, 122.9, 108.0, 21.2; ESI-MS: m/z 289
(M+H)+, HRMS (ESI) m/z [M+H]+ calcd for C14H10O3N2Cl = 289.03745
found 289.03727.
2-(4-bromo-2-nitrophenyl)benzo[d]oxazole (2t): [16a] Yellow solid, mp.
158-159 °C, 1H NMR (400 MHz, CDCl3) δ: 8.06 (d, J = 8.42 Hz, 1H), 8.00
(d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.43 Hz, 1H), 7.83-7.80 (m, 1H), 7.59 -
7.57 (m, 1H), 7.44 -7.38 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 157.8,
150.9, 149.3, 141.5, 135.4, 132.3, 127.2, 126.3, 125.6, 125.1, 120.8,
120.0, 110.1.
1-Methyl-2-(2-nitrophenyl)-1H-benzo[d]imidazole (2u): [12j] Yellow solid,
mp. 125-126 °C; 1H NMR (400 MHz, CDCl3) δ: 8.20 (d, J = 4.73 Hz, 1H),
7.78 (m, 2H), 7.72 (m, 1H), 7.65 (d, J = 4.9 Hz, 1H), 7.41 (d, J = 4.6 Hz,
1H), 7.31 (m, 2H), 3.61 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 149.7,
148.6, 142.7, 135.6, 133.5, 131.1, 125.9, 124.7, 123.2, 122.5, 120.1,
109.6, 30.5.
Acknowledgements
BV thanks the University Grant Commission (UGC), New Delhi
for the award of Senior Research Fellowship (SRF).
[6]
a) T. Piou, T. Rovis, Nature 2015, 527, 86; b) X.-H. Liu, H. Park, J.-H.
Hu, Y. Hu, Q.-L. Zhang, B.-L. Wang, B. Sun, K.-S. Yeung, F.-L. Zhang,
J.-Q. Yu, J. Am. Chem. Soc 2017, 139, 888; c) K. Raghuvanshi, D. Zell,
L. Ackermann, Org. Lett 2017, 19, 1278; d) J. Li, S. Warratz, D. Zell, S.
De Sarkar, E. E. Ishikawa, L. Ackermann, J. Am. Chem. Soc. 2015, 137,
13894; e) J. M. Neely, T. Rovis, J. Am. Chem. Soc 2014, 136, 2735–
2738; f) A. Mandal, H. Sahoo, S. Dana, M. Baidya, Org. Lett. 2017, 19,
4138.
Keywords: copper • chelation assisted • benzazoles • nitration •
fluorogenic
[1]
[2]
a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
Weinheim, 2001; b) T. Mori, H. Suzuki, Synlett 1995, 1995, 383; c) J. W.
Mcdonald, G. D. Friesen, W. E. Newton, Inorganica Chim. Acta 1986,
121, 33; d) G. A. Olah, P. Ramaiah, C. B. Rao, G. Sandford, R. Golam,
N. J. Trivedi, J. A. Olah, J. Am. Chem. Soc. 1993, 115, 7246; e) L.
Melone, C. Punta, Beilstein J. Org. Chem. 2013, 9, 1296.
[7]
a) A. A. Weekes, A. D. Westwell, Curr. Med. Chem. 2009, 16, 2430; b)
G. W. Bemis, M. A. Murcko, J. Med. Chem. 1996, 39, 2887; c) J. S.
Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Biomol. Chem.
2006, 4, 2337; d) D. S. Surry, S. L. Buchwald, Angew. Chemie Int. Ed.
2008, 47, 6338; e) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew.
Chemie Int. Ed. 2005, 44, 4442.
a) J. Gui, C.-M. Pan, Y. Jin, T. Qin, J. C. Lo, B. J. Lee, S. H. Spergel, M.
E. Mertzman, W. J. Pitts, T. E. La Cruz, Science. 2015, 348, 886; b) W.
Zhang, J. Xie, B. Rao, M. Luo, J. Org. Chem. 2015, 80, 3504; c) T. B.
Nguyen, L. Ermolenko, P. Retailleau, A. Al‐Mourabit, Angew. Chemie
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701187
European Journal of Organic Chemistry
FULL PAPER
[8]
a) S. M. Sondhi, N. Singh, A. Kumar, O. Lozach, L. Meijer, Bioorg. Med.
Chem. 2006, 14, 3758; b)Y. Leng, F. Yang, W. Zhu, Y. Wu, X. Li, Org.
Biomol. Chem. 2011, 9, 5288.
[9]
a) M. Manafi, W. Kneifel, S. Bascomb, Microbiol. Rev. 1991, 55, 335; b)
S. Orenga, A. L. James, M. Manafi, J. D. Perry, D. H. Pincus, J.
Microbiol. Methods 2009, 79, 139; c) M. Manafi, Int. J. Food Microbiol.
2000, 60, 205.
[10] a) M. Cellier, A. Gignoux, A. L. James, S. Orenga, J. D. Perry, S. N.
Robinson, S. P. Stanforth, G. Turnbull, Bioorg. Med. Chem. Lett. 2015,
25, 5694; b) M. Cellier, O. J. Fabrega, E. Fazackerley, A. L. James, S.
Orenga, J. D. Perry, V. L. Salwatura, S. P. Stanforth, Bioorg. Med.
Chem. 2011, 19, 2903–2910.
[11] B. V Pipaliya, A. K. Chakraborti, J. Org. Chem. 2017, 82, 3767–3780.
[12] a) N. Khatun, A. Banerjee, S. K. Santra, A. Behera, B. K. Patel, RSC
Adv. 2014, 4, 54532; b) S. K. Santra, A. Banerjee, N. Khatun, B. K.
Patel, European J. Org. Chem. 2015, 2015, 350; c) A. Banerjee, S. K.
Santra, S. Guin, S. K. Rout, B. K. Patel, European J. Org. Chem. 2013,
2013, 1367; d) M. Choi, J. Park, N. K. Mishra, S.-Y. Lee, J. H. Kim, K.
M. Jeong, J. Lee, Y. H. Jung, I. S. Kim, Tetrahedron Lett. 2015, 56,
4678; e) Y. Ping, Z. Chen, Q. Ding, Y. Peng, Synthesis, 2017, 49, 2015;
f) Q. Ding, H. Ji, C. Ye, J. Wang, J. Wang, L. Zhou, Y. Peng,
Tetrahedron 2013, 69, 8661; g) Q. Ding, H. Ji, Z. Nie, Q. Yang, Y. Peng,
J. Organomet. Chem. 2013, 739, 33; h) P. Ranjan Mohanta, A.
Banerjee, S. Kumar Santra, A. Behera, B. K. Patel, Adv. Synth. Catal.
2016, 358, 2047 i) K. Seth, M. Nautiyal, P. Purohit, N. Parikh, A. K.
Chakraborti, Chem. Commun. 2015, 51, 191; j) H.-J. Qiao, F. Yang, S.-
W. Wang, Y.-T. Leng, Y.-J. Wu, Tetrahedron 2015, 71, 9258.
[13] a) V. Botla, D. V. Ramana, B. Chiranjeevi, M. Chandrasekharam,
Chemistry Select, 2016, 1, 3974; b) M. Chandrasekharam, B.
Chiranjeevi, K. S. V. Gupta, B. Sridhar, J. Org. Chem. 2011, 76,
10229; c) B. Chiranjeevi, G. Koyyada, S. Prabusreenivasan, V. Kumar,
P. Sujitha, C. G. Kumar, B. Sridhar, S. Shaik, M. Chandrasekharam,
RSC Adv. 2013, 3, 16475; d) B. Chiranjeevi, B. Vinayak, T.
Parsharamulu, V. S. Phanibabu, B. Jagadeesh, M. Chandrasekharam,
Eur. J. Org. Chem. 2014, 35, 7839; e) K. S. V. Gupta, D. V. Ramana, B.
Vinayak, B. Sridhar M. Chandrasekharam, New J. Chem. 2016, 40,
6389; f) D. V. Ramana, M. Chandrasekharam, ChemistrySelect, 2017,
2, 2241; g) B. Vinayak, M. Chandrasekharam, Org. Lett, 2017,19, 3528;
h) B. Vinayak, M. A. Reddy, B. Chiranjeevi, M. Chandrashekharam, Y.
Poornachandra, G. C. Kumar, Indian J.chem. Sec B 2016, 55B, 461.
[14] a) Z.-G. Niu, T. Zheng, Y.-H. Su, P.-J. Wang, X.-Y. Li, F. Cui, J. Liang
and G.-N. Li, New J. Chem., 2015, 39, 6025; b) V. Dhayalan, M.
Hayashi, Synthesis, 2012, 44, 2209.
[15] a) L. Zhang, Z. Liu, H. Li, G. Fang, B.-D. Barry, T. A. Belay, X. Bi, Q.
Liu, Org. Lett. 2011, 13, 6536; b) E. Kianmehr, Y. A. Lomedasht, N.
Faghih, K. M. Khan, J. Org. Chem 2016, 81, 6087; c) P. Sadhu, S. K.
Alla, T. Punniyamurthy, J. Org. Chem 2015, 80, 8245.
[16] a) L. Chen, L. Ju, K. A. Bustin, J. M. Hoover, Chem. Commun. 2015, 51,
15059; b) K. Yang, P. Wang, C. Zhang, A. A. Kadi, H. Fun, Y. Zhang, H.
Lu, European J. Org. Chem. 2014, 2014, 7586.
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Entry for the Table of Contents (Please choose one layout)
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Key Topic*
Botla Vinayak, Akudari Ashok and
Malapaka Chandrasekharam*
Page No. – Page No.
Copper-Catalyzed Chelation
Assisted ortho-Nitration of 2- Aryls
with Pharmacophoric Benzo-
thiazoles and -oxazoles as Directing
Groups.
Text for Table of Contents
A Copper-catalyzed chelation assisted ortho-nitration of aryls with benzazoles i.e., benzoxazoles, benzthiazoles and
benzimidazoles as efficient pharmacophorically important directing groups has been achieved. This nitration protocol employs
inexpensive and environmentally friendly reagents and highlights the operational simplicity, functional group tolerance and
high regioselectivity.
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