Pyrroline Synthesis via Visible-Light-Promoted Hydroimination of Unactivated Alkenes with N,N′-Dimethylpropylene Urea as H-Donor

Article abstract of DOI:10.1002/adsc.201700937

Synthesis of 3,4-pyrroline derivatives via visible-light-induced hydro/oxyimination of unactivated olefins is reported. In the presence of the photoredox catalyst fac-Ir(ppy)₃, the key iminyl radical intermediate can be readily generated from O-acyl oximes, and undergoes intramolecular cyclization and H-abstraction from solvent or is trapped by TEMPO to give the corresponding hydro/oxyimination product, respectively. Mechanistic investigations indicate that N,N′-dimethylpropylene urea (DMPU) works as both reducing agent for catalyst regeneration and H-donor for product formation in this process. (Figure presented.).

Full text of DOI:10.1002/adsc.201700937

Title: Pyrroline Synthesis via Visible-Light-Promoted Hydroimination
of Unactivated Alkenes with N,N'-Dimethylpropyleneurea as H-
Donor
Authors: Sai-Hu Cai, Ding-Xing Wang, Lu Ye, Ze-Yao Liu, Chao Feng,
and Teck-Peng Loh
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
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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: Adv. Synth. Catal. 10.1002/adsc.201700937
Link to VoR: http://dx.doi.org/10.1002/adsc.201700937

Advanced Synthesis & Catalysis
10.1002/adsc.201700937
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Pyrroline Synthesis via Visible-Light-Promoted Hydroimination
of Unactivated Alkenes with N,N'-Dimethylpropylene Urea as
H-Donor
a,b
a
a
a
a,
Sai-Hu Cai, Ding-Xing Wang, Lu Ye, Ze-Yao Liu, Chao Feng, * and Teck-Peng
b c,
Loh , *
a
Institute of Advanced Synthesis (IAS), College of Chemistry and Molecular Engineering, Jiangsu National Synergetic
Innovation Center for Advanced Materials (SICAM), Nanjing Tech University, 30 South Puzhu Road, Nanjing 211800,
People’s Republic of China
E-mail: iamcfeng@njtech.edu.cn
Department of Chemistry, University of Science and Technology of China (USTC), 96 Jin Zhai Road, Hefei, Anhui
b
2
30026, People’s Republic of China
c
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technolog-
ical University (NTU), SPMS-CBC-05-20, 21 Nanyang Link, Singapore 637371, Singapore
E-mail: teckpeng@ntu.edu.sg
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Synthesis of 3,4-pyrroline derivatives via visible- In the past few years, visible light photoredox
light-induced hydro/oxyimination of unactivated olefins is catalysis, which makes use
reported. In the presence of the photoredox catalyst fac-
3
Ir(ppy) , the key iminyl radical intermediate can be readily
generated from O-acyl oximes, and undergoes
intramolecular cyclization and H-abstraction from solvent
or is trapped by TEMPO to give the corresponding
hydro/oxyimination product, respectively. Mechanistic
investigations indicate that N,N'-dimethylpropylene urea
(
DMPU) works as both reducing agent for catalyst
regeneration and H-donor for product formation in this
process.
Keywords: N-heterocycles; visible light; photoredox
catalysis; iminyl radicals; C-N bond
Scheme 1. Photocatalytic Hydroimination of Unactivated
Alkenes.
of sunlight or artificial light (visible light) as a
renewable energy source, has emerged as a powerful
and feasible tool for the generation of various N-
Nitrogen-centered radicals (NCRs) are known as
versatile intermediates for the construction of N-
containing compounds which have found broad
application in chemical, material, medical and life
sciences.[ In this context, an enormous effort has
been made toward the development of C-N bond
[4]
radical species. Recent work reported by Nicewicz,
Knowles, Xiao and Leonori have already
demonstrated the synthetic potential of photoredox
1]
[5]
generated N-radicals in olefin hydroamination.
[1d]
formation methodologies based on NCRs.
However,
the
photoredox-catalysis-enabled
Specifically, as an important subclass, iminyl radicals
are also widely capitalized on for the preparation of
hydroimination protocol via iminyl radicals remains
largely underexplored mainly due to the lack of
simple and reliable methods for the iminyl radical
generation. Recently, several groups have described
advances in addressing this challenging issue. For
instance, acyl oxime and organic azide have been
shown as effective iminyl radical precursors under
[2]
imines and nitrogen-containing heterocycles.
Traditionally, N-centered radicals are generated by
thermolysis or photolysis in which hazardous radical
initiators, elevated temperature, or high-energy UV
irradiation are always required.[ Therefore, the
development of mild and environmentally friendly
1a]
[6]
the photoredox catalysis conditions by Leonori,
[3]
protocols has received growing attention recently.
[7]
[8]
[9]
[10]
[11]
[13]
Yu,
Zhou,
Nevado,
Fu,
Studer,
[12]
Pan/Zhou/Han
and our group (Scheme 1a).
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700937
Despite these significant achievements, there still
remains ample room for the exploitation of such
radical species in hydroimination of alkenes in view
of the economical and ecological advantages of this
strategy. Herein, we would like to report a visible-
light-promoted hydroimination of unactivated alkenes
with DMPU as H-donor for the synthesis of 3,4-
pyrroline derivatives (Scheme 1b).
Initially,
we
selected
the
O-(4-
trifluoromethylbenzoyl)oxime 1a[14] as model
substrate to test the feasibility of the intramolecular
hydroimination by using fac-Ir(ppy) as photocatalyst
under the irradiation of a 23 W fluorescent household
bulb (Table 1). Pleasingly we found that by using
DMF as solvent, the desired hydroimination product
2a was obtained in 60% yield, while CH
MeOH and CHCl only led to low yields or no
product (Table 1, entries 1-6). As expected, the
reaction efficiency could be further enhanced by
employing 1,4-cyclohexadiene as an additional H-
donor (Table 1, entries 7 and 8). NMP and DMA
were found to be effective solvents, however,
decreased yields were observed (Table 1, entries 9
3
3
CN, THF,
3
Table 1. Optimization of Reaction Conditions[a]
entry photocatalyst
solvent
DMF
yield
60%
45%
1
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
3
3
3
3
3
3
3
3
3
3
2[b]
DMF
3
3
CH CN 20%
4
THF
15%
6%
0
5
MeOH
6
CHCl
3
7[c]
8[c]
9
DMF
75%
3
CH CN 50%
NMP
DMA
62%
55%
1
0
11
fac-Ir(ppy)
3
DMPU 84%(72%)[d]
1 [
1 [
2
e]
f]
fac-Ir(ppy)
fac-Ir(ppy)
DMPU
DMC
67%
4%
3%
12%
22%
0
3
3
3
1
1
1
4
5
6
Ru(bpz)
Ir(ppy) (dtbbpy)PF
Eosin Y
3
(PF
6
)
2
DMPU
DMPU
DMPU
DMPU
DMPU
2
6
1 [
7
g]
h]
fac-Ir(ppy)
3
1 [
8
-
0
[
a]
Unless otherwise noted, the reactions were carried out at
room temperature under argon atmosphere using 1a (E/Z
mixture, 0.1 mmol), photocatalyst (0.002 mmol) in solvent
1
(
1 mL) for 12 h with yields being determined by H NMR
using mesitylene as internal standard.
[
[
[
[
[
[
[
b]
c]
d]
e]
f]
Air condition.
.0 equiv 1,4-cyclohexadiene as additive.
Isolated yield.
.5 mL of DMPU was used.
.0 equiv DMPU was added as additive.
2
0
3
g]
h]
[a]
Use fac-Ir(ppy)
3
as photocatalyst run in dark.
Isolated yield.
Z-configuration substrate.
E-configuration substrate.
NMR yields were determined by crude H NMR using
[b]
No photocatalyst.
[
[
c]
d]
PG
=
4-(trifluoromethyl)benzoyl, DMF
=
N,N-
1
dimethylformamide, THF = tetrahydrofuran, NMP = N-
methylpyrrolidone, DMA N,N-dimethylacetamide,
DMPU = N,N'-dimethylpropylene urea, DMC = dimethyl
=
mesitylene as an internal standard.
PG = 4-(trifluoromethyl)benzoyl.
Reaction conditions: unless otherwise noted, 1 (E/Z
carbonate.
3
mixture, 0.1 mmol), fac-Ir(ppy) (2 mol%, 0.002 mmol) in
DMPU (1 mL) under argon was stirred at room
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700937
the consumption of the starting material.[15] To
demonstrate the practicality of this transformation,
we carried out a 5 mmol scale reaction and the
desired hydroimination product 2g was isolated in
temperature overnight (12 h) in front of a 23 W fluorescent
household bulb.
Scheme 2. Reaction Scope.
87% yield (Scheme 3).
and 10). To our delight, the yield of 2a increased to
8
4% in DMPU (Table 1, entry 11). The yield of 2a
declined to 67% by increasing the concentration
Table 1, entry 12). Given the promotion effect of
(
DMPU, it was employed as additive in the reaction
with dimethyl carbonate as solvent, however, only a
trace amount of 2a was obtained (Table 1, entry 13).
In addition, photocatalysts were screened and fac-
Scheme 3. Large Scale Reaction.
Ir(ppy) proved to be superior to the others for this
3
[
6a]
According to Leonori’s report and our previous
study,
transformation (Table 1, entries 14-16). Furthermore,
control experiments revealed the observed reactivity
of 1a was associated with the visible-light
photocatalytic activation. Without either light or
photocatalyst, no product could be detected and the
starting material was recovered completely (Table 1,
entries 17 and 18).
[13]
the C-centered radical generated via
intramolecular cyclization initiated iminyl radical is
believed to be a key intermediate in the process. In
order to lend concrete evidence for the existence of
these C-centered radical as well as potentially provide
more
diversified
modes
for
alkene
difunctionalization, further investigation aiming at
synthetic elaboration of C-centered radical was
executed. As expected, addition of 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) to the model
reaction resulted in the formation of an oxyimination
product 3aa in 84% yield (Scheme 4). This finding
suggests that the process does involve radical
intermediates. Moreover this reaction mode offers an
opportunity to develop photocatalytic oxyimination
of unactivated olefins. Subsequently, the scope of the
oxyimination was evaluated with the O-acyl oxime
With the optimized conditions in hand (Table 1,
entry 9), the substrate scope with respect to O-acyl
oximes 1 was investigated and the results were
summarized in Scheme 2. A large variety of
decorated (Me-, MeO-, halo-, F C-, MeOCO- and
3
amido-bearing) aryl O-acyl oximes successfully
underwent the intramolecular hydroimination to
afford the corresponding products in good to
excellent yields (64-98%), regardless of the location
and electronic property of substituents on the
aromatic ring (2a-p). Substrates bearing naphthyl or
heteroaryl substituents were also applicable to this
transformation (2q and 2r). The influence of α-
substituents to this reaction was also probed as in the
cases of 1s and 1t. 3,4-Pyrroline 2s and 2t were
obtained in 80% and 95% yields respectively,
indicating the Thorpe-Ingold effect plays a part in
this cyclization process. Then the substrate scope was
smoothly extended to O-acyl oximes having a di- or
trisubstituted alkene pendant. The yield of
hydroimination were only marginally affected by the
steric bulkiness at alkene moiety (2u, 2v). Notably,
when 1w was employed, the reaction proceeded
stereoselectively to afford a single diastereoisomer in
high yield (2w). Moreover, alkyl and alkynyl based
substrates also proved to be amenable to this reaction.
1g, 1j, 1o-q, 1w. All examined substrates gave the
oxyimination products
For
example,
the
2-naphthylmethyl
and
phenoxymethyl derived O-acyl oximes were found to
be competent for this reaction, albeit with diminished
reaction efficiency (2x, 34% and 2z-1, 40%, NMR
yield). In the case of phenylethynyl-substituted
substrate, 2y could be obtained in modest yield.
However, when alkenyl based substrates 1z was
subjected into the standard reaction conditions only
[
[
[
[
a]
b]
c]
d]
Isolated yield.
.2 equiv TEMPO.
.5 equiv TEMPO.
.0 equiv TEMPO.
1
1
2
PG = 4-(trifluoromethyl)benzoyl.
14% yield of desired product could be detected with
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700937
Reaction conditions: 1 (E/Z mixture, 0.1 mmol), TEMPO
intermediate III donates a single electron towards
IV
(
3
x equiv), fac-Ir(ppy) (2 mol%, 0.002 mmol) in DMPU (1
[
[
Ir ] to regenerate the original catalytic species
mL) under argon was stirred at room temperature
overnight (12 h) in front of a 23 W fluorescent household
bulb.
III [16]
Ir ].
On the other hand, in the presence of
TEMPO the generation of oxyimination product 3
through carbon-centered radical trapping is
kinetically more favorable (path 2).
Scheme 4. Oxyimination via C-centered Radical Trapping
with TEMPO.
in good to excellent yields (3ga, 3ja, 3oa-qa).
Notably, when 1w was employed, the reaction also
proceeded selectively to afford
diastereoisomer (3wa).
a
single
To gain further insight into this photoredox
catalytic system, we first performed luminescence
quenching experiments and found that O-acyl oxime
3+
derivative quenched [fac-Ir(ppy) ]* luminescence
3
effectively. It is suggested that the iminyl radical
intermediate could be generated by the photo
irradiation. The photocatalytic oxyimination of O-
acyl oxime derivative with TEMPO further
confirmed that the iminyl radical intermediate is
involved in the reaction which undergo 5-exo-trig
cyclization to produce pyrroline species containing a
primary carbon-centered radical. To identify the
hydrogen source of the desired product 2, the
Scheme 6. Plausible Reaction Mechanism.
In summary, we have developed a mild, general
and scalable method for hydro/oxyimination of
unactivated olefins through photoredox catalysis.
This strategy provides an efficient synthetic pathway
to 3,4-pyrroline derivatives via C-N bond formation.
A wide variety of substrates are well accommodated
in this reaction and afford the desired products in
moderate to excellent yields simply by irradiation
with visible light in the presence photocatalyst at
ambient temperature. In addition, mechanism studies
revealed the triple roles of DMPU as solvent, H-
donor and reductant in this transformation.
reactions with 1u and 1p were run in DMF-d
DMF with D O (10.0 equiv) additive, respectively
Scheme 5). It was found that these two reactions
afforded 2u-D in 35% yield and 2p-D in 61% yield
58% D). These results strongly indicate that it is the
7
and
2
(
(
solvent rather than the adventitious amount of water
that acts as hydrogen source in this reaction.
Experimental Section
An oven-dried Schlenk tube equipped with a stirring bar
was charged with oxime ester (1 equiv, 0.1 mmol) and fac-
3
Ir(ppy) (2 mol%, 0.002 mmol). After refilling with argon
repeated three times, DMPU (1 mL) was added via a
syringe. Then the mixture was stirred at room temperature
overnight (12 h) in front of a 23 W fluorescent household
bulb at ambient temperature. Upon the completion of the
Scheme 5. Deuterium-Labeling Experiments.
3
reaction, saturated aq. NaHCO (5 mL) and EtOAc (10
mL) were added. The layers were separated and the
aqueous layer was extracted with EtOAc. The combined
organic layers were then washed with brine, dried
(Na SO ) and concentrated in vacuo. The crude residue
Based on the mechanistic study, we propose that
the reaction is initiated through facile oxidative
2
4
*
III
IV
was purified by flash column chromatography on silica gel
to afford the corresponding product.
quenching of the photoexcited [ Ir ] to [Ir ] by
oxime derivative 1 with the concomitant generation
of the iminyl radical intermediate I (Scheme 6). The
ensuing 5-exo-trig cyclization of I occurs to produce
carbon-centered radical species II. At this juncture,
there are two possible reaction pathways depending
on the reaction conditions. In path 1, the hydrogen
atom transfer from DMPU to intermediate II affords
the the hydroimination product 2, and then the radical
Acknowledgements
We thank the “1000-Youth Talents Plan”, a Start-up Grant
(
39837110) from Nanjing Tech University and financial support
by SICAM Fellowship by Jiangsu National Synergetic Innovation
Center for Advanced Materials.
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201700937
References
H. Jiang, R. Wang, S. Yu, J. Org. Chem. 2016, 81,
7
276-7281.
8] Q. Wang, J. Huang, L. Zhou, Adv. Synth. Catal. 2015,
57, 2479-2484.
9] W. Shu, C. Nevado, Angew. Chem. Int. Ed. 2017, 56,
881-1884.
[
1] a) S. Z. Zard, Chem. Soc. Rev. 2008, 37, 1603-1608;
b) S. H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem.
Soc. Rev. 2011, 40, 5068-5083; c) B. Q. Sire, S. Z.
Zard, Beilstein J. Org. Chem. 2013, 9, 557-576; d)
T. Xiong, Q. Zhang, Chem. Soc. Rev. 2016, 45,
[
[
[
[
[
[
[
[
3
1
10] J. Li, P. Zhang, M. Jiang, H. Yang, Y. Zhao, H. Fu,
Org. Lett. 2017, 19, 1994-1997.
11] H. Jiang, A. Studer, Angew. Chem. Int. Ed. 2017, 56,
3
069-3087.
[
2] For reviews, see: a) M. Kitamura, K. Narasaka, Bull.
Chem. Soc. Jpn. 2008, 81, 539-547; b) J. C. Walton,
Acc. Chem. Res. 2014, 47, 1406-1416; c) J. C. Walton,
Molecules 2016, 21, 63-85; d) H.-W. Huang, H.-W. Cai,
G.-J. Deng, Org. Biomol. Chem. 2016, 14, 1519-1530.
3] J.-R. Chen, X.-Q. Hu, L.-Q. Lu, W.-J. Xiao, Chem.
Soc. Rev. 2016, 45, 2044-2056.
4] For reviews, see: a) T. P. Yoon, M. A. Ischay, J. Du,
Nature Chem. 2010, 2, 527-532; b) J. M. R. Narayanam,
C. R. J. Stephenson, Chem. Soc. Rev. 2011, 40, 102-
1
2273-12276.
12] P. Qian, Y. Deng, H. Mei, J. Han, J. Zhou, Y. Pan,
Org. Lett. 2017, 19, 4798-4801.
13] S.-H. Cai, J.-H. Xie, S. Song, L. Ye, C. Feng, T.-P.
Loh, ACS Catal. 2016, 6, 5571-5574.
14] See the supporting information for the screening of
the protecting group of oxime.
15] To expand the application of the present
hydroimination reaction, an intermolecular reaction
[
[
1
13; c) C. K. Prier, D. A. Rankic, D. W. C. MacMillan,
with
diphenylmethanone
O-(4-
Chem. Rev. 2013, 113, 5322-5363; d) D. Ravelli, M.
Fagnoni, A. Albini, Chem. Soc. Rev. 2013, 42, 97-113;
e) M. N. Hopkinson, B. Sahoo, J.-L. Li, F. Glorius,
Chem. -Eur. J. 2014, 20, 3874-3886; f) N. A. Romero,
D. A. Nicewicz, Chem. Rev. 2016, 116, 10075-10166;
g) M. D. Kärkäs, J. A., Jr. Porco, C. R. J. Stephenson,
Chem. Rev. 2016, 116, 9683-9747.
(
trifluoromethyl)benzoyl) oxime 1-z2 and but-3-en-1-
ylbenzene and the reaction aiming to prepare 6-
membered heterocycles with 1-phenylhex-5-en-1-one
O-(4-(trifluoromethyl)benzoyl) oxime 1-z3 were
examined under the optimized conditions, however, no
desired product was obtained in either reaction.
[
5] For examples of photoredox-mediated olefin hydroami-
nation, see: a) T. M. Nguyen, D. A. Nicewicz, J. Am.
Chem. Soc. 2013, 135, 9588-9591; b) T. M. Nguyen, N.
Manohar, D. A. Nicewicz, Angew. Chem. Int. Ed. 2014,
5
3, 6198-6201; c) A. J. Musacchio, L. Q. Nguyen, G. H.
Beard, R. R. Knowles, J. Am. Chem. Soc. 2014, 136,
2217-12220; d) Q.-X. Hu, J.-R. Chen, Q. Wei, F.-L.
1
Liu, Q.-H. Deng, A. M. Beauchemin, W.-J. Xiao,
Angew. Chem. Int. Ed. 2014, 53, 12163-12167; e) N. J.
Gesmundo, J. M. Grandjean, D. A. Nicewicz, Org. Lett.
2
015, 17, 1316-1319; f) D. C. Miller, G. J. Choi, H. S.
Orbe, R. R. Knowles, J. Am. Chem. Soc. 2015, 137,
3492-13495; g) J. Davies, T. D. Svejstrup, D. F. Reina,
N. S. Sheikh, D. Leonori, J. Am. Chem. Soc. 2016, 138,
092-8095; h) A. J. Musacchio, B. C. Lainhart, X.
1
[
16] C. Dai, F. Meschini, J. M. R. Narayanam, C. R. J.
Stephenson, J. Org. Chem. 2012, 77, 4425-4431. In our
reaction the crude reaction mixture was analyzed by
LC-MS and NMR, however no valuable information
was obtained to reveal the end state of DMPU.
8
Zhang, S. G. Naguib, T. C. Sherwood, R. R. Knowles,
Science 2017, 355, 727-730; i) D. F. Reina, E. M. Dau-
ncey, S. P. Morcillo, T. D. Svejstrup, M. V. Popescu, J.
J. Douglas, N. S. Sheikh, D. Leonori, Eur. J. Org.
Chem. 2017, 2108-2111.
[
[
6] a) J. Davies, S. G. Booth, S. Essafi, R. A. W. Dryfe, D.
Leonori, Angew. Chem. Int. Ed. 2015, 54, 14017-14021.
b) J. Davies, N. S. Sheikh, D. Leonori, Angew. Chem.
Int. Ed. 2017, 56, 13361-13365.
7] a) X. Sun, J. Li, Y. Ni, D. Ren, Z. Hu, S. Yu, Asian J.
Org. Chem. 2014, 3, 1317-1325; b) H. Jiang, X.-D. An,
K. Tong, T.-Y. Zheng, Y. Zhang, S.-Y. Yu, Angew.
Chem. Int. Ed. 2015, 54, 4055-4059; c) X.-D. An, S.
Yu, Org. Lett. 2015, 17, 2692-2695; d) X. Sun, S. Yu,
Chem. Commun. 2016, 52, 10898-10901; e) Y.-Y. Han,
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201700937
UPDATE
Pyrroline Synthesis via Visible-Light-Promoted
Hydroimination of Unactivated Alkenes with N,N'-
Dimethylpropyleneurea as H-Donor
Adv. Synth. Catal. Year, Volume, Page – Page
a,b
a
a
Sai-Hu Cai, Ding-Xing Wang, Lu Ye, Ze-Yao
a
a,
b c,
Liu, Chao Feng, * and Teck-Peng Loh , *
6
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