Rh(III)-Catalyzed Enaminone-Directed C-H Coupling with α-Diazo-α-phosphonoacetate for Reactivity Discovery: Fluoride-Mediated Dephosphonation for C-C Coupling Reactions

Article abstract of DOI:10.1021/acs.orglett.8b01406

Rh(III)-catalyzed enaminone-directed C-H coupling with α-diazo-α-phosphonoacetate has been used for the identification of fluoride-mediated dephosphonation C-C coupling reactivity for the synthesis of 4-hydroxy-1-naphthoates. Intermolecular C-C coupling of α-phosphonoacetate and benzaldehyde for (E)-selective α,β-unsaturated ester synthesis has also been achieved.

Full text of DOI:10.1021/acs.orglett.8b01406

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh(III)-Catalyzed Enaminone-Directed C−H Coupling with α‑Diazo-α-
phosphonoacetate for Reactivity Discovery: Fluoride-Mediated
Dephosphonation for C−C Coupling Reactions
Chao Song, Chen Yang, Hua Zeng, Wenjing Zhang, Shan Guo, and Jin Zhu*
Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing University, Nanjing 210023, China
S
* Supporting Information
ABSTRACT: Rh(III)-catalyzed enaminone-directed C−H
coupling with α-diazo-α-phosphonoacetate has been used
for the identification of fluoride-mediated dephosphonation
C−C coupling reactivity for the synthesis of 4-hydroxy-1-
naphthoates. Intermolecular C−C coupling of α-phospho-
noacetate and benzaldehyde for (E)-selective α,β-unsaturated
ester synthesis has also been achieved.
Scheme 1. Rh(III)-Catalyzed Enaminone-Directed C−H
Coupling with α-Diazo-α-phosphonoacetate for the
Identification of Fluoride-Mediated Dephosphonation C−C
Coupling Reactivity
ransition-metal-catalyzed directed C−H functionalization
1
Thas proven useful for organic synthesis but has never
been invoked as a designated reactivity discovery tool. We are
interested in both reaction development using novel directing
groups2 and subsequent identification of distinct reactivity
between the directing group and installed group.3 In particular,
the exploration of functional group reactivity at the post C−H
functionalization stage allows the expansion of experimental
parameter space to the otherwise incompatible region with
respect to C−H functionalization. This can provide a fertile
ground for reactivity discovery. We have recently demon-
strated the use of enaminone as a directing synthon for
Rh(III)- and Co(III)-catalyzed C−H coupling with α-diazo-β-
ketoester, alkyne,2a and dioxazolone.3a The intriguing push−
pull electronic character of the enaminone permits versatile
C−C and C−N coupling ring-closure formation of carbocyclic
and heterocyclic frameworks. We envisioned that the high C−
H functionalization directing capability and unique electro-
philic reactivity associated with the enaminone moiety should
allow its use as a survey handle for the examination of
complementary reactivity for the installed group (Scheme 1).
Herein, Rh(III)-catalyzed enaminone-directed C−H coupling
with α-diazo-α-phosphonoacetates identifies fluoride-mediated
dephosphonation reactivity as an enabling tool for intra-
molecular C−C coupling synthesis of 4-hydroxy-1-naphthoates
(Scheme 1). In addition, intermolecular C−C coupling
reactivity has been demonstrated for α-phosphonoacetates
and benzaldehydes, providing rapid access to (E)-selective α,β-
unsaturated esters (Scheme 1).
achievements include Wittig reaction5 (phosphonium ylide),
Horner reaction6 (phosphine oxide), Wadsworth−Emmons
reaction7 (phosphonate), and Seyferth−Gilbert reaction8
(diazophosphonate). These reactions are driven by the high
oxophilic reactivity of a phosphorus atom9 and typically require
the use of a strong base for deprotonation generation of
nucleophilic carbanion. In pursuit of a distinct reactivity profile
enabled by the phosphorus moiety, preferably under mild
conditions, we have turned our attention to the fluoride ion.
Organophosphorus compounds are useful synthons for
Received: May 3, 2018
diverse types of chemical transformations.4 Notable synthetic
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01406
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Organic Letters
Letter
The switching of conventional strongly basic conditions to
essentially neutral fluoride ion conditions should allow the
achievement of high functional group tolerance. The fluoride
ion (e.g., in tetra-n-butylammonium fluoride, or TBAF) has
been traditionally used as a highly effective reagent for the
cleavage of an Si−O bond10 (desilylation of O-silyl ether to the
parent alcohol) due to the high fluorophilicity of a silicon
atom. Only recently has fluoride ion been exploited in the
context of phosphonate-based chemistry.11 A one-pot, two-step
reaction has been used to incorporate a radioactive moiety into
target compound, but neither substrate scope nor reaction
mechanism was investigated.11 Although α-diazo-β-carbonyl
phosphonates have been shown to undergo chemical trans-
formations with the participation of fluoride ion, the reactivity
is demonstrated only when both carbon atom and diazo
moiety are involved ([3 + 2] cycloaddition), and no direct C−
C coupling reactivity is confirmed to be viable.12 Also,
evidence for the dephosphonation is not unambiguously
Scheme 2. Substrate Scope of Rh(III)-Catalyzed C−H
a,b
Functionalization Reaction
1
conclusive from the H NMR (not clean, area integration
value for protons not actually in ratio) and HRMS (subjected
to interference from other nonrelevant species) data, each
respectively for the two sketched mechanistic fragments.
Reaction development described herein establishes fluoride-
mediated dephosphonation for C−C coupling reactions and its
compatibility with diversely ranged functional groups.
We commenced the investigation of an Rh(III)-catalyzed
C−H functionalization reaction by examining experimental
conditions for the coupling of two model substrates, 3-
(dimethylamino)-1-phenylprop-2-en-1-one (1a, 1 equiv) and
ethyl 2-diazo-2-(diethoxyphosphoryl)acetate (2a, 1.2 equiv)
(Table S1). With 2 mol % [RhCp*Cl2]2, 8 mol % AgSbF6, and
10 mol % KOAc as the catalytic system, screening of reaction
media shows 2,2,2-trifluoroethanol (TFE) as the optimum
solvent. Target C−H functionalization product 3a can be
generated in 76% yield after 8 h reaction at 60 °C and 92%
yield can be achieved at room temperature (rt). Variation of
KOAc quantity and replacement of KOAc by either other
bases or HOAc provide no beneficial effect.
With the reaction conditions optimized, we next explored
the substrate scope for the C−H functionalization reaction
(Scheme 2). Using 2a as the coupling partner, an inspection of
enaminones containing a wide range of substituents on the
phenyl ring reveals high functional group tolerance and high
product yield. For para substitution, all electron-rich (Me, 1b;
OMe, 1c; Ph, 1d) and electron-poor (F, 1e; Cl, 1f; Br, 1g; I,
1h; CF3, 1i; CO2Me, 1j; NO2, 1k; CN, 1l; methanesulfonyl, or
Ms, 1m) substrates show excellent performance, furnishing the
respective target product in generally over 90% or even
quantitative yield (except for 1l, 84% yield). The reactivity for
meta-substituted substrates (Me, 1n; OMe, 1o; F, 1p; Cl, 1q;
Br, 1r; NO2, 1s) varies as compared to the para-substituted
counterparts: 1n and 1r are superior over 1b and 1g; 1o and 1s
are inferior to 1c and 1k; 1p and 1q are comparable to 1e and
1f. The regioselectivity is also substrate-dependent. Although
both 1n and 1p give a single regioisomer, the site selectivity is
opposite. The C−C coupling for 1n occurs at the sterically less
hindered site, but the sterically more demanding coupling is
observed for 1p. All other meta-substituted substrates (1o, 1q−
s) provide a mixture of regioisomers, likely reflecting a
competing operation of electronic and steric factors. The
reaction can likewise proceed efficiently for the ortho-
substituted substrate (F, 1t). Further, an equally high yield is
observed for both electron-rich (OMe, 1u) and electron-poor
a
Conditions: 1 (0.2 mmol, 1 equiv), 2 (0.24 mmol, 1.2 equiv), TFE
b
c
d
(1 mL). Isolated yields. 1.5 equiv of 2a, 40 °C. 4 h.
(F, 1v) disubstituted substrates. The change of alkyl group on
ester (Me, 2w) and phosphonate (Me, 2x) does not alter the
coupling reactivity with 1a. It is worth noting that for certain
substrates a slight deviation from the optimized reaction
conditions is in demand. An addition of 1.5 equiv of 2a (or
2w) and an elevation of the reaction temperature to 40 °C are
helpful for reactions involving 1c, 1j−l, 1n, 1q−s (or 1a), and
the reaction time can be reduced to 4 h in the case of 1d, 1i,
1p, and 1v.
With the high-yield C−H functionalization reaction
established, we sought to discover novel reactivity for the
C−H functionalization-installed group. With the installed
group resembling one coupling partner of the Wadsworth−
Emmons reaction, the starting point is the confirmation of
enaminone moiety as an appropriate handle for reactivity
discovery. The electrophilic reactivity for enaminone is
demonstrated, using 3a as the model substrate, by the ability
to generate carbanion on the installed group through base-
mediated deprotonation for intramolecular C−C coupling
reaction (Table 1). The reaction was set for testing at 60 °C in
THF with 3 equiv of base. No target product 4a is observed
under BuOK, BuOLi, K2CO3, N,N-diisopropylethylamine
(DIPEA), and 4-(dimethylamino)pyridine (DMAP) after 16
h. The addition of MeONa enables the occurrence of
cyclization in 59% yield, but with half of the ester ethyl
group exchanged to a methyl group (entry 1, Table 1). The
replacement of MeONa by EtONa offers no improvement in
product yield (entry 2, Table 1). The switching to a non-
nucleophilic base, tBuONa, can significantly boost the product
yield (87%), but over half of the ester group is hydrolyzed to
acid due to the strong basicity (entry 3, Table 1). The increase
t
t
t
of BuONa quantity to 5 equiv can deliver the cyclization
product in pure acid form, but with the product yield
diminished to 61% (entry 4, Table 1). Further exhaustive
assessment with NaH and LiCl (2 equiv)/1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU, 5 equiv) witnesses the
stagnation of product yield in the less than 60% regime (entries
5 and 6, Table 1). Taken together, the various issues
engendered by traditionally used bases prompt a thorough
B
DOI: 10.1021/acs.orglett.8b01406
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Organic Letters
Letter
smoothly, generally delivering the 4-hydroxy-1-naphthoate
derivatives in excellent yield. The strongly electron-with-
drawing NO2 group (3k) provides the best outcome (98%
yield), but the reactivity for iodo-substituted substrate (3h) is
not ideal. The reaction for meta-substituted substrates (3n−s)
is also efficient, with sterically less hindered substrates (3na,
3oa, 3qa−sa) exhibiting superior reactivity over sterically more
hindered ones (3ob, 3qb). The ortho substitution (3t)
diminishes the product yield as compared to the para (3e)
and meta (3pb) counterparts. Interestingly, disubstitution (3u,
3v) endows a higher substrate reactivity than monosubstitution
(3c, 3e, 3oa). For the alkyl group on ester (3w) and
phosphonate (3x), the product yield is more sensitive to a
change on the phosphonate site. Taken together, the fluoride-
mediated deprotonation method provides as-expected mild
synthetic conditions for a broadly functional group-tolerant
coupling reaction.
To investigate the fluoride-mediated cyclization mechanism,
1a and ethyl 2-phenyl-2-(diethoxyphosphoryl)acetate (5) were
independently subjected to rt TBAF (10 equiv) treatment in
THF. Product 1a is 95% recovered after 24 h (eq S1), and 5
generates a dephosphonated product 6 in 91% yield
(protonation step at the workup stage for the production of
6) and FPO(OEt)2 after 10 h (eq 1, Scheme 4). Also, the
Table 1. Optimization of Reaction Conditions for
Cyclization Reaction
a,b
entry
base (equiv)
MeONa (3)
EtONa (3)
tBuONa (3)
tBuONa (5)
NaH (3)
LiCI (2)+DBU (5)
TBAF (3)
TBAF (10)
temp (°C)
time (h)
yield (%)
c
1
2
3
4
5
6
7
8
9
60
60
60
60
60
60
60
60
rt
16
16
16
16
16
16
16
16
24
59
60
87
d
e
61
57
43
35
82
TBAF (10)
92
a
b
Conditions: 1a (0.2 mmol, 1 equiv), base, THF (2 mL). Isolated
c
d
yields. Ethyl ester/methyl ester = 1:1.1 were obtained. Ethyl ester/
acid = 1:1.5 were obtained. Acid product was obtained.
e
overhaul of the carbanion generation system. Instead of relying
on deprotonation, the strong P−F bond can offer a potentially
feasible alternative means for achieving a fluoride-mediated
dephosphonation C−C coupling reactivity. Indeed, the
participation of TBAF allows the C−C coupling cyclization
synthesis of 4a in the desired ester-intact form. The product
yield can be increased from 35% to 82% with an increase of
TBAF quantity from 3 equiv to 10 equiv (entries 7 and 8,
Table 1; likely, 10 equiv TBAF to drive the equilibrium
forward). The lowering of temperature to rt and the extension
of reaction time to 24 h can further increase the yield to 92%
(entry 9, Table 1).
Scheme 4. Mechanistic Investigation for Fluoride-Mediated
Cyclization Reaction
With the fluoride-mediated C−C coupling cyclization
demonstrated for 3a, we next examined the functional group
compatibility under the mild TBAF synthetic conditions
(Scheme 3). For all the para-substituted C−H functionaliza-
tion substrates (3b−m), the cyclization reaction can proceed
Scheme 3. Substrate Scope of Fluoride-Mediated
a,b
Cyclization Reaction
conversion from 3a to 4a is accompanied by the production of
FPO(OEt)2 (eq 2, Scheme 4). The observations are consistent
with the initial direct abstraction of phosphonate group by the
fluoride ion. This novel reactivity pattern is not identified for a
typical base. For example, treatment of 5 with EtONa (3
equiv) leads to a 99% recovery (eq 3, Scheme 4), and
treatment of 5 with NaOH (3 equiv) fails to generate 6 or its
hydrolyzed acid product (eq S5). The abstraction of the
phosphonate group is not preceded by a deprotonation step, as
a combination of EtONa (1 equiv) and TBAF (1 equiv) only
allows the trace conversion of 3a to 4a (eq S6). Taken
together, these experimental results support the following
cyclization mechanism (Scheme 5): abstraction of phospho-
nate group by fluoride, nucleophilic Michael addition-type C−
Scheme 5. Proposed Mechanism for Fluoride-Mediated
Cyclization Reaction
a
Conditions: 3a−x (0.2 mmol, 1 equiv), TBAF (1 M in THF, 2 mL).
b
isolated yields.
C
DOI: 10.1021/acs.orglett.8b01406
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Organic Letters
Letter
C coupling ring closure attack on dimethylamino-linked
carbon atom and formation of oxygen-centered anionic
species, elimination of dimethylamino group along with α-
proton adjacent to the ester group and aromatization
formation of naphthalene skeleton, and completion of the
product synthesis with protonation.
Significantly, the utility of fluoride-mediated dephosphona-
tion C−C coupling reactivity is not restricted to intramolecular
reaction. Intermolecular C−C coupling reaction can also be
effected based on this reaction pathway, as manifested in the
nucleophilic attack on the aldehyde group (Scheme 6). A
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01406.
■
S
Experimental procedure; characterization of the prod-
ucts (PDF)
1H and 13C NMR spectra of selected products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jinz@nju.edu.cn.
ORCID
Scheme 6. Substrate Scope of Fluoride-Mediated
a,b
Intermolecular C−C Coupling Reaction
Jin Zhu: 0000-0003-4681-7895
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Natural
Science Foundation of China (21425415, 21774056) and the
National Basic Research Program of China (2015CB856303).
REFERENCES
■
(1) (a) Zheng, J.; Wang, S.-B.; Zheng, C.; You, S.-L. Angew. Chem.,
Int. Ed. 2017, 56, 4540. (b) Zhao, Y.; Li, S.; Zheng, X.; Tang, J.; She,
Z.; Gao, G.; You, J. Angew. Chem., Int. Ed. 2017, 56, 4286. (c) Dooley,
J. D.; Lam, H. W. Chem. - Eur. J. 2018, 24, 4050. (d) Chirila, P. G.;
Adams, J.; Dirjal, A.; Hamilton, A.; Whiteoak, C. J. Chem. - Eur. J.
2018, 24, 3584. (e) Cai, Z.-J.; Liu, C.-X.; Gu, Q.; You, S.-L. Angew.
Chem., Int. Ed. 2018, 57, 1296. (f) Bu, Q.; Rogge, T.; Kotek, V.;
Ackermann, L. Angew. Chem., Int. Ed. 2018, 57, 765. (g) Gao, M.;
Yang, Y.; Chen, H.; Zhou, B. Adv. Synth. Catal. 2018, 360, 100.
(h) Martinez, A. M.; Rodriguez, N.; Gomez-Arrayas, R.; Carretero, J.
C. Chem. - Eur. J. 2017, 23, 11669. (i) Muniraj, N.; Prabhu, K. R. Adv.
Synth. Catal. 2018, 360, 1370. (j) Nallagonda, R.; Thrimurtulu, N.;
Volla, C. M. R. Adv. Synth. Catal. 2018, 360, 255.
(2) (a) Zhou, S.; Wang, J.; Wang, L.; Song, C.; Chen, K.; Zhu, J.
Angew. Chem., Int. Ed. 2016, 55, 9384. (b) Liu, B.; Fan, Y.; Gao, Y.;
Sun, C.; Xu, C.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 468.
(3) (a) Yu, X.; Chen, K.; Wang, Q.; Guo, S.; Zha, S.; Zhu, J. Angew.
Chem., Int. Ed. 2017, 56, 5222. (b) Liu, B.; Song, C.; Sun, C.; Zhou,
S.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 16625.
a
Conditions: 7 (0.24 mmol, 1.2 equiv), 8a−r (0.2 mmol, 1 equiv),
b
TBAF (1 M in THF, 2 mL). Isolated yields.
reaction between ethyl 2-(diethoxyphosphoryl)acetate (7) and
benzaldehyde (8a) can occur highly efficiently at 30 °C,
furnishing the target (E)-specific α,β-unsaturated ester product
9a in 84% within 4 h. An inspection of the para-substituted
benzaldehydes shows that although electron-donating groups
(Me, 8b; OMe, 8c) can enhance the reactivity, the effect of
electron-withdrawing groups (F, 8d; Cl, 8e; Br, 8f; CF3, 8g) is
uncertain. The product yield can reach quantitative level with
8f, but is not satisfactory with 8g. All of the meta-substituted
substrates (Me, 8h; OMe, 8i; F, 8j; Cl, 8k; Br, 8l) can react
highly effectively. For para- and meta-substituted substrates,
exclusive (E)-specific reactivity is observed. The ortho-
substituted substrates (OMe, 8m; F, 8n; Cl, 8o; Br, 8p)
provide a mixture of (E)- and (Z)-isomers, with (E)-isomers as
the dominant products. The disubstituted substrates (8q, 8r)
exhibit an intriguingly very high (E)-specific reactivity.
In summary, we have used transition-metal-catalyzed C−H
functionalization as a reactivity discovery tool for the
identification of a fluoride-mediated dephosphonation C−C
coupling reactivity. Both intramolecular C−C coupling syn-
thesis of 4-hydroxy-1-naphthoates and intermolecular C−C
coupling synthesis of (E)-selective α,β-unsaturated esters have
been facilely achieved. The mild reaction conditions of
fluoride-based protocol contrasts with the strong basic
conditions required in a conventional deprotonation-initiated
reaction sequence, thus featuring high functional group
compatibility. The new reactivity pattern identified for the
phosphonate group opens up a new avenue for C−C coupling
chemistry.
(4) (a) Lao, Z.; Toy, P. H. Beilstein J. Org. Chem. 2016, 12, 2577.
(b) Karanam, P.; Reddy, G. M.; Koppolu, S. R.; Lin, W. Tetrahedron
Lett. 2018, 59, 59.
(5) (a) Yang, S.; Wang, C.; Lin, C.; Karanam, P.; Reddy, G. M.; Tsai,
Y.; Lin, W. Angew. Chem., Int. Ed. 2018, 57, 1668. (b) Zhang, K.; Lu,
L.; Yao, S.; Chen, J.; Shi, D.; Xiao, W. J. Am. Chem. Soc. 2017, 139,
12847. (c) Zeng, X.; Cao, Z.; Wang, X.; Chen, L.; Zhou, F.; Zhu, F.;
Wang, C.; Zhou, J. J. Am. Chem. Soc. 2016, 138, 416. (d) Lee, H.;
Kang, T.; Lee, H.-Y. Angew. Chem., Int. Ed. 2017, 56, 8254.
(6) (a) Zhang, K.; Cai, L.; Yang, Z.; Houk, K. N.; Kwon, O. Chem.
Sci. 2018, 9, 1867. (b) Meyer, D.; Rentsch, L.; Marti, R. RSC Adv.
2014, 4, 32327.
(7) (a) Chatare, V. K.; Andrade, R. B. Angew. Chem., Int. Ed. 2017,
56, 5909. (b) Tsakos, M.; Clement, L. L.; Schaffert, E. S.; Olsen, F.
N.; Rupiani, S.; Djurhuus, R.; Yu, W.; Jacobsen, K. M.; Villadsen, N.
L.; Poulsen, T. B. Angew. Chem., Int. Ed. 2016, 55, 1030. (c) Yoshida,
M.; Saito, K.; Kato, H.; Tsukamoto, S.; Doi, T. Angew. Chem., Int. Ed.
2018, 57, 5147.
(8) (a) Nishimaru, T.; Kondo, M.; Takeshita, K.; Takahashi, K.;
Ishihara, J.; Hatakeyama, S. Angew. Chem., Int. Ed. 2014, 53, 8459.
(b) Zhang, W.; Ding, M.; Li, J.; Guo, Z.; Lu, M.; Chen, Y.; Liu, L.;
Shen, Y.; Li, A. J. Am. Chem. Soc. 2018, 140, 4227.
D
DOI: 10.1021/acs.orglett.8b01406
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) Byrne, P. A.; Gilheany, D. G. Chem. Soc. Rev. 2013, 42, 6670.
́
́
(b) García Lopez, J. G.; Ramallal, A. M.; Gonzalez, J.; Roces, L.;
́
̃
García-Granda, S.; Iglesias, M. J.; Ona-Burgos, P.; Lopez Ortiz, F. L. J.
Am. Chem. Soc. 2012, 134, 19504. (c) Byrne, P. A.; Gilheany, D. G. J.
Am. Chem. Soc. 2012, 134, 9225.
(10) (a) Schuppe, A. W.; Huang, D.; Chen, Y.; Newhouse, T. R. J.
Am. Chem. Soc. 2018, 140, 2062. (b) Kwon, Y.; Schulthoff, S.; Dao, Q.
M.; Wirtz, C.; Fuerstner, A. Chem. - Eur. J. 2018, 24, 109. (c) Hayashi,
Y.; Koshino, S.; Ojima, K.; Kwon, E. Angew. Chem., Int. Ed. 2017, 56,
11812. (d) Wang, C.; Oki, M.; Nishikawa, T.; Harada, D.; Yotsu-
Yamashita, M.; Nagasawa, K. Angew. Chem., Int. Ed. 2016, 55, 11600.
(11) Takashima, M.; Kato, K.; Ogawa, M.; Magata, Y. RSC Adv.
2013, 3, 21275.
(12) Phatake, R. S.; Mullapudi, V.; Wakchaure, V. C.; Ramana, C. V.
Org. Lett. 2017, 19, 372.
E
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