Synthesis of Tribenzo[b,e,g]phosphindole Oxides via Radical Bicyclization Cascades of o-Arylalkynylanilines

Article abstract of DOI:10.1021/acs.orglett.7b02071

A new DTBP/Mg(NO₃)₂-mediated bicyclization cascade of o-arylalkynylanilines with secondary arylphosphine oxides has been developed, enabling dual C(sp²)-H functionalization along with the cleavage of the C-N bond. The combination between regioselective P-centered radical-triggered [3 + 2] cyclization and C-centered radical-induced cross-coupling in a one-pot manner delivered 27 examples of tribenzo[b,e,g]phosphindole oxides with generally high regioselectivity. A reasonable mechanism for forming such products involving radical addition-cyclization cascade is proposed.

Full text of DOI:10.1021/acs.orglett.7b02071

Letter
pubs.acs.org/OrgLett
Synthesis of Tribenzo[b,e,g]phosphindole Oxides via Radical
Bicyclization Cascades of o‑Arylalkynylanilines
Jie Li,† Wen-Wen Zhang,† Xiao-Jing Wei,† Wen-Juan Hao,*,† Guigen Li,‡ Shu-Jiang Tu,*,†
and Bo Jiang*,†
†School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou 221116, P. R. China
‡Institute of Chemistry & BioMedical Sciences, Nanjing University, Nanjing 210093, P. R. China
S
* Supporting Information
ABSTRACT: A new DTBP/Mg(NO3)2-mediated bicyclization
cascade of o-arylalkynylanilines with secondary arylphosphine oxides
has been developed, enabling dual C(sp2)−H functionalization along
with the cleavage of the C−N bond. The combination between
regioselective P-centered radical-triggered [3 + 2] cyclization and C-
centered radical-induced cross-coupling in a one-pot manner
delivered 27 examples of tribenzo[b,e,g]phosphindole oxides with
generally high regioselectivity. A reasonable mechanism for forming such products involving radical addition−cyclization cascade
is proposed.
Scheme 1. Profiles for P-Centered Radical Cyclization
s a highly important and valuable class of phosphorus-
Acontaining heterocycles, fused benzophosphole derivatives
have attracted considerable attention in organic chemistry and
material science due to their unique physical and optical
properties,1 which show great potential in optoelectrochemical
materials.2 Consequently, substantial effort has been made
toward identifying efficient methods for the preparation of such
compounds. Generally, the vast majority of well-established
synthetic strategies for benzophosphole syntheses include
nucleophilic substitution of a P−X bond with organolithium or
organomagnesium reagents,3 metal-catalyzed [2 + 2 + 2]
cycloaddition of dialkynylphosphines with polyynes,4 intra-
molecular cross-coupling of aryl halides with hydrophosphines,5
dehydrogenative cyclization of hydrophosphine oxides,6 palla-
dium-catalyzed cyclization of triarylphosphines,7 and multiple
cyclizations of o-halide-substituted arylalkynes with phenyl-
phosphorus compounds.8 Specifically, the group of Miura9a and
Duan9b independently reported the Ag-mediated arylphosphine
oxide radical-triggered cyclization of symmetrical diarylalkynes,
providing direct approaches toward benzo[b]phosphole oxides
in an atom-economic fashion (Scheme 1a). Later, various
catalytic variations of such reactions were developed using
different oxidants.10 However, studies in the reactivity of
unsymmetrical diarylalkynes have been almost ignored. Recently,
Tang et al. described a silver-mediated cycloaddition between N-
Ts-2-alkynylanilines and secondary phosphine oxides to access 3-
phosphinoylindole derivatives (Scheme 1b).11 To further
investigate the regioselectivity of this radical cyclization and
expand the family of benzophospholes, N-unprotected o-
arylalkynylanilines were subjected to a reaction with diary-
lphosphine oxides in order to establish a regioselective radical [3
+ 2] cyclization (Scheme 1c). Unexpectedly, regiosiomers of
pentacyclic tribenzo[b,e,g]phosphindole oxides 3 and 3′ were
generated in a functional-group-compatible manner through
dual C(sp2)−H functionalization along with the cleavage of the
C−N bond without observation of the desired benzo[b]-
phosphole oxides 4 as we originally planned (Scheme 1d).
This protocol represents the first bicyclization procedure for the
direct synthesis of these new pentacyclic tribenzo[b,e,g]-
phosphindole oxides by merging a regioselective P-centered
radical-triggered [3 + 2] cyclization with C-centered radical-
induced cross-coupling in a one-pot manner. Herein, we would
report this serendipitous and interesting radical transformation.
Phosphine oxide radicals from HP(O)R1R2 precursor show
high reactivity with unsaturated bonds and behave as ideal radical
partners for constructing organophosphorus molecules.12 At the
Received: July 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02071
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Letter
outset of our studies, diphenylphosphine oxide 2a was selected as
a phosphine oxide radical donor and subjected to the reaction of
2-((4-chlorophenyl)ethynyl)aniline 1a as unsymmetrical diary-
lalkyne substrate using silver nitrate (AgNO3, 2.0 equiv) as a
promoter. The reaction smoothly proceeded in 1,4-dioxane at
100 °C under air conditions. Instead of the desired benzo[b]-
phosphole oxide 4a, unexpected inseparable tribenzo[b,e,g]-
phosphindole oxide isomers 3a and 3a′ in a 98:2 ratio were
provided in total 56% yield, which were fully characterized by
NMR spectroscopic analysis (Table 1, entry 1). In view of this
ybenzoate (TBPB), and K2S2O8 were chosen to evaluate
improvement in the yield of isomers. The experimental results
indicated that all these oxidants can drive the reaction to access
products 3a and 3a′ (entries 8−11), in which DTBP was proven
to be most efficient for this oxidative system (72%, entry 8). By
taking the combination of DTBP with Mg(NO3)2·6H2O, we
then investigated the solvent effect by using other aprotic
solvents, such as acetonitrile (CH3CN), tetrahydrofuran (THF),
1,2-dichloroethane (DCE), and toluene, showing that all these
solvents have no positive effect on the yield of 3a as compared
with 1,4-dioxane (entries 12−15 vs entry 8). The reaction
efficiency was found to show an important temperature
dependence. With the temperature at 80 °C, this transformation
hardly occurred to deliver the desired product (entry 16),
whereas the relatively lower conversion into isomers 3a and 3a′
was observed as the reaction was conducted at either 90 or 110
°C (entries 17 and 18).
a
Table 1. Optimization of Reaction Conditions
With these optimal reaction conditions in hand, we then
systematically studied the generality of this DTBP/Mg(NO3)2-
mediated bicyclization cascade toward tribenzo[b,e,g] phosphin-
dole oxides 3 by examining o-arylalkynylaniline and phosphine
oxide components (Scheme 2). At first, o-arylalkynylanilines
with diverse functionalities were evaluated in combination with
phosphine oxide 2a. Substituents with both electronically poor
and rich properties at different positions of the arylalkynyl (R2)
moiety would be accommodated, confirming the success of
transformations, as the corresponding regioisomers 3a−g and
3a′−g′ were afforded in 37−72% yields and 88:12−98:2 ratios.
Functional groups such as chloride (1a), fluoride (1b), bromide
(1c), methyl (1d), ethyl (1e), methoxy (1f), and ester (1g) were
compatible with the oxidative conditions. Alternatively, 2-
(phenylethynyl)aniline 1h was an efficient reaction partner,
enabling its radical-triggered [3 + 2] cyclization/cross-deami-
nated coupling cascade to access product 3h as a sole isomer in
88% yield. The reaction can be extended to different functional
groups such as chloride (1i and 1j), fluoride (1k), bromide (1l
and 1m), cyano (1n), trifluoromethyl (1o), and methyl (1p and
1q) located at the 4- or 5-positions of the aniline ring, and
structurally diverse isomers 3i−q and 3i′−q′ in 32−62% yields
and 91:9 to >99:1 ratios were rendered under the DTBP/
Mg(NO3)2-mediated conditions. Among them, the presence of
strong electron-withdrawing groups such as fluoride, cyano, and
trifluoromethyl proved to be more reluctant to undergo the
bicyclization process, in which 3k and 3n,o were generated in
substantially decreased yields of 32−37%. Moreover, the
electronic nature of substituents on both the aniline ring (R1)
and arylalkynyl (R2) moieties was also probed. The reaction
occurred smoothly with a variety of functional groups on both
aryl moieties, giving access to isomers 3r−v and 3r′−v′ with
yields ranging from 36% to 69%, some of which were offered with
an excellent regioselectivity (3r−t in >99:1 ratio).
b
entry
oxidant (equiv)
solvent
temp (°C)
yield (%)
c
1
AgNO3 (2.0)
AgOAc (2.0)
AgOAc (2.0)
AgOAc (2.0)
AgOAc (2.0)
AgOAc (2.0)
AgOTf (2.0)
DTBP (2.0)
TBHP (2.0)
TBPB (2.0)
K2S2O8 (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH3CN
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
56
c
2
trace
41
3
d
4
18
e
5
13
f
6
trace
7
51
8
72
9
58
10
11
12
13
14
15
16
17
18
54
49
trace
trace
trace
48
THF
DCE
toluene
g
1,4-dioxane
1,4-dioxane
1,4-dioxane
ND
90
39
66
110
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), oxidant (2.0
equiv), Mg(NO3)2·6H2O (2.0 equiv), solvent (5.0 mL), under air
conditions. Isolated total yield based on substrate 1a. Without
Mg(NO3)2·6H2O. Use of Zn(NO3)2·6H2O (2.0 equiv). Use of
Co(NO3)2·6H2O (2.0 equiv). Use of Cu(NO3)2·3H2O (2.0 equiv).
b
c
d
e
f
g
ND = not detected.
interesting result, we worked to improve the efficiency of this
deaminated bicyclization reaction. Exchanging AgNO3 for
AgOAc completely suppressed the formation of 3a and 3a′,
but 3-phosphinoylindole 5a (21%) was obsvered,11 indicating
that nitrate anions play a key role in this transformation (entry 2).
Next, we considered employing magnesium nitrate as nitrate
anion source to investigate the feasibility of this transformation.
As we expected, the reaction in the presence of 2.0 equiv of
Mg(NO3)2·6H2O gave a 41% yield of 3a and 3a′ (entry 3). Other
nitrate salts including Zn(NO3)2·6H2O, Co(NO3)2·6H2O, and
Cu(NO3)2·3H2O gave very inferior outcomes13 (entries 4−6).
Employment of silver trifluoromethanesulfonate (AgOTf)
resulted in 51% yield of isomers 3a and 3a′ but still relatively
low compared with AgNO3 (entry 7 vs entry 1). Instead of silver
salt oxidants, four other oxidants including di-tert-butyl peroxide
(DTBP), tert-butyl hydroperoxide (TBHP), tert-butyl perox-
Next, the scope with respect to the phosphine oxide
component was investigated. The bicyclization reaction can
tolerate various phosphine oxides 2b−e carrying both electron-
deficient (Cl, 2b) and electron-rich (Me, 2c and 2d; MeO, 2e)
groups at different positions of arene rings, leading to the
formation of tribenzo[b,e,g]phosphindole oxides 3w−z in
moderate yields (Scheme 2). Cyclohexyl(phenyl)phosphine
oxide 2f was also found to be a suitable coupling partner and
can be transformed into cyclohexyl-substituted product 3aa in
64% yield. It is noteworthy that the current oxidative protocol
represents a new and practical pathway for assembling richly
decorated tribenzo[b,e,g]phosphindole oxides 3 with generally
B
DOI: 10.1021/acs.orglett.7b02071
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Organic Letters
Letter
a
Scheme 2. Substrate Scope for Synthesis of Products 3
Scheme 3. Control Experiments
cross-deaminated coupling step. Notably, radical inhibitors
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and butylhy-
droxytoluene completely suppressed the reaction and provided
TEMPO-P and BHT-P adducts (detected by LC−MS analysis),
respectively (Scheme 3b,c), suggesting that the [3 + 2]
cyclization involves a radical mechanism. To confirm the
mechanism of deaminated coupling, 4-methoxyaniline 8 was
subjected to 1,1-diphenyl ethylene under the standard conditions
with observation of the desired product 9 by LC−MS analysis
(Scheme 3d). These outcomes supported a radical process for
deaminated coupling.
On the basis of our own observations and literature survey,9−11
a reasonable radical-triggered mechanism was proposed as
depicted in Scheme 4. First, a P-centered radical A is generated in
Scheme 4. Plausible Reaction Pathway
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), DTBP (2.0 equiv),
Mg(NO3)2·6H2O (2.0 equiv), 1,4-dioxane (5.0 mL), under air
b
c
conditions. Isolated total yield based on substrate 1. Regioisomer
ratio based on the analysis of 31P NMR.
excellent regioselectvity through DTBP/Mg(NO3)2-mediated
bicyclization cascade involving deaminated C(sp2)−H function-
alization. In the case of 3j, its structure was unequivocally
confirmed by carrying out single-crystal X-ray diffraction (see the
Supporting Information).
Some control experiments were conducted to gain mecha-
nistic insight into this bicyclization. N-Protected o-arylalkynyla-
nilines 6a−c were treated with 2a under the standard conditions,
and the corresponding benzo[b]phosphole oxides 7a−c as a
single regioisomer were isolated in 45−56% yields. The
regioselectivity may depend on its hydrogen bonds and steric
effects (Scheme 3a), showing that protected amines inhibit cross-
deaminated coupling; [3 + 2] cyclization occurred prior to the
situ from diphenylphosphine oxide 2a through single-electron
transfer (SET) mediated by the homolysis of DTBP under
heating conditions.14 Next, regioselective addition of radical A to
alkynyl unit of o-arylalkynylanilines 1 favors a vinyl radical B
(route i), depending on hydrogen bonds and steric effect,
followed by homolytic aromatic substitution (HAS B to D) to
C
DOI: 10.1021/acs.orglett.7b02071
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Organic Letters
Letter
(f) Bouit, P. A.; Escande, A.; Szucs, R.; Szieberth, D.; Lescop, C.;
̋
generate benzo[b]phosphole oxide D. Intermediate D mediated
by Mg(NO3)2 and tert-butoxyl radical (tBuO•) may provide
intermediate E, although this transformation is unclear for us so
far, which gives the phenyl radical F by decomposition of itself
Nyulas
(g) Chen, H.; Delaunay, W.; Li, J.; Wang, Z.; Bouit, P. A.; Tondelier, D.;
Geffroy, B.; Mathey, F.; Duan, Z.; Reau, R.; Hissler, M. Org. Lett. 2013,
́ ́
zi, L.; Hissler, M.; Reau, R. J. Am. Chem. Soc. 2012, 134, 6524.
́
15, 330. (h) Cordaro, J. G.; Stein, D.; Grutzmacher, H. J. Am. Chem. Soc.
̈
t
with concurrent release of N2 and BuO•. Phenyl radical F
2006, 128, 14962. (i) Berger, O.; Petit, C.; Deal, E. L.; Montchamp, J. L.
undergoes a second HAS (F to 3) to access final major product 3.
The formation of minor product 3′ undergoes a radical process
very similar to that mentioned above (route ii).
Adv. Synth. Catal. 2013, 355, 1361.
́
(2) For reviews, see: (a) Baumgartner, T.; Reau, R. Chem. Rev. 2006,
106, 4681. (b) Matano, Y.; Imahori, H. Org. Biomol. Chem. 2009, 7,
1258. (c) Mathey, F. Acc. Chem. Res. 2004, 37, 954.
In conclusion, we have established a new radical-triggered
bicyclization of o-arylalkynylanilines with a large variety of
functional groups by which a series of structurally diverse
tribenzo[b,e,g]phosphindole oxides with generally high regiose-
lectivity would be synthesized through double C(sp2)−H
functionalization. This reaction merged P-centered radical-
triggered [3 + 2] cyclization with C-centered radical-induced
cross-coupling in a one-pot manner, resulting in multiple C−P
and C−C bond-forming events along with C−N cleavage of
aniline susbstrates. The protocol features bond-forming/
annulation efficiency and functional group tolerance, providing
a direct and powerful synthetic method for constructing
phosphorus-containing heterocycles. Further investigation on
the mechanism of this radical bicyclization is underway in our
laboratory.
(3) For examples, see: (a) Chen, R.-F.; Fan, Q.-L.; Zheng, C.; Huang,
W. Org. Lett. 2006, 8, 203. (b) Geramita, K.; McBee, J.; Tilley, T. D. J.
Org. Chem. 2009, 74, 820. (c) Fukazawa, A.; Kiguchi, M.; Tange, S.;
Ichihashi, Y.; Zhao, Q.; Takahashi, T.; Konishi, T.; Murakoshi, K.; Tsuji,
Y.; Staykov, A.; Yoshizawa, K.; Yamaguchi, S. Chem. Lett. 2011, 40, 174.
(4) (a) Fukawa, N.; Osaka, T.; Noguchi, K.; Tanaka, K. Org. Lett. 2010,
12, 1324. (b) Sawada, Y.; Furumi, S.; Takai, A.; Takeuchi, M.; Noguchi,
K.; Tanaka, K. J. Am. Chem. Soc. 2012, 134, 4080.
(5) Nakano, K.; Oyama, H.; Nishimura, Y.; Nakasako, S.; Nozaki, K.
Angew. Chem., Int. Ed. 2012, 51, 695.
(6) (a) Kuninobu, Y.; Yoshida, T.; Takai, K. J. Org. Chem. 2011, 76,
7370. (b) Kuninobu, Y.; Origuchi, K.; Takai, K. Heterocycles 2012, 85,
3029. (c) Feng, C.-G.; Ye, M.; Xiao, K.-J.; Li, S.; Yu, J.-Q. J. Am. Chem.
Soc. 2013, 135, 9322. (d) Li, C.; Yano, T.; Ishida, N.; Murakami, M.
Angew. Chem., Int. Ed. 2013, 52, 9801.
(7) Baba, K.; Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52,
11892.
ASSOCIATED CONTENT
* Supporting Information
■
(8) (a) Tsuji, H.; Sato, K.; Ilies, L.; Itoh, Y.; Sato, Y.; Nakamura, E. Org.
Lett. 2008, 10, 2263. (b) Sanji, T.; Shiraishi, K.; Kashiwabara, T.;
Tanaka, M. Org. Lett. 2008, 10, 2689. (c) Fukazawa, A.; Ichihashi, Y.;
Kosaka, Y.; Yamaguchi, S. Chem. - Asian J. 2009, 4, 1729. (d) Hayashi, Y.;
Matano, Y.; Suda, K.; Kimura, Y.; Nakao, Y.; Imahori, H. Chem. - Eur. J.
2012, 18, 15972.
(9) (a) Unoh, Y.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int.
Ed. 2013, 52, 12975. (b) Chen, Y.-R.; Duan, W.-L. J. Am. Chem. Soc.
2013, 135, 16754.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02071.
Experimental procedures and spectroscopic data for all
new compounds 3a−aa and 7a−c (PDF)
X-ray crystal data for 3j (CIF)
X-ray crystal data for 7c (CIF)
(10) (a) Quint, V.; Morlet-Savary, F.; Lohier, J. F.; Lalevee, J.;
Gaumont, A. C.; Lakhdar, S. J. Am. Chem. Soc. 2016, 138, 7436.
(b) Zhang, P.; Gao, Y.; Zhang, L.; Li, Z.; Liu, Y.; Tang, G.; Zhao, Y. Adv.
Synth. Catal. 2016, 358, 138. (c) Ma, D.; Chen, W.; Hu, G.; Zhang, Y.;
Gao, Y.; Yin, Y.; Zhao, Yu. Green Chem. 2016, 18, 3522. (d) Ma, W.;
Ackermann, L. Synthesis 2014, 46, 2297.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wjhao@jsnu.edu.cn
*E-mail: laotu@jsnu.edu.cn.
*E-mail: jiangchem@jsnu.edu.cn.
(11) Gao, Y.; Lu, G.; Zhang, P.; Zhang, L.; Tang, G.; Zhao, Y. Org. Lett.
2016, 18, 1242.
ORCID
(12) For selected examples, see: (a) Zhu, Y.-L.; Wang, D.-C.; Jiang, B.;
Hao, W.-J.; Wei, P.; Wang, A.-F.; Qiu, J.-K.; Tu, S.-J. Org. Chem. Front.
2016, 3, 385. (b) Sun, J.; Qiu, J.-K.; Wu, Y.-N.; Hao, W.-J.; Guo, C.; Li,
G.; Tu, S.-J.; Jiang, B. Org. Lett. 2017, 19, 754. (c) Zhu, X.-T.; Zhao, Q.;
Liu, F.; Wang, A.-F.; Cai, P.-J.; Hao, W.-J.; Tu, S.-J.; Jiang, B. Chem.
Commun. 2017, 53, 6828. (d) Kong, W.; Merino, E.; Nevado, C. Angew.
Chem., Int. Ed. 2014, 53, 5078. (e) Liu, C.; Zhu, M.; Wei, W.; Yang, D.;
Cui, H.; Liu, X.; Wang, H. Org. Chem. Front. 2015, 2, 1356. (f) Peng, P.;
Lu, Q.; Peng, L.; Liu, C.; Wang, G.; Lei, A. Chem. Commun. 2016, 52,
12338. (g) Hu, G.; Shan, C.; Chen, W.; Xu, P.; Gao, Y.; Zhao, Y. Org.
Lett. 2016, 18, 6066. (h) Chen, S.; Zhang, P.; Shu, W.; Gao, Y.; Tang, G.;
Zhao, Y. Org. Lett. 2016, 18, 5712.
Guigen Li: 0000-0002-9312-412X
Bo Jiang: 0000-0003-3878-515X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC (Nos.
21232004, 21472071, and 21602087), PAPD of Jiangsu Higher
Education Institutions, the Outstanding Youth Fund of JSNU
(YQ2015003), NSF of Jiangsu Province (BK20151163 and
BK20160212), the Qing Lan Project, and NSF of Jiangsu
Education Committee (15KJB150006).
(13) Li, Y.-M.; Sun, M.; Wang, H.-L.; Tian, Q.-P.; Yang, S.-D. Angew.
Chem., Int. Ed. 2013, 52, 3972.
(14) Ouyang, X.-H.; Song, R.-J.; Liu, B.; Li, J.-H. Adv. Synth. Catal.
2016, 358, 1903.
REFERENCES
■
(1) (a) Fukazawa, A.; Yamaguchi, S. Chem. - Asian J. 2009, 4, 1386.
(b) Ren, Y.; Baumgartner, T. J. Am. Chem. Soc. 2011, 133, 1328. (c) Ren,
Y.; Kan, W.-H.; Henderson, M. A.; Bomben, P. G.; Berlinguette, C. P.;
Thangadurai, V.; Baumgartner, T. J. Am. Chem. Soc. 2011, 133, 17014.
(d) Matano, Y.; Saito, A.; Fukushima, T.; Tokudome, Y.; Suzuki, F.;
Sakamaki, D.; Kaji, H.; Ito, A.; Tanaka, K.; Imahori, H. Angew. Chem., Int.
Ed. 2011, 50, 8016. (e) Bruch, A.; Fukazawa, A.; Yamaguchi, E.;
Yamaguchi, S.; Studer, A. Angew. Chem., Int. Ed. 2011, 50, 12094.
D
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