Synthesis of Fluorescent Azafluorenones and Derivatives via a Ruthenium-Catalyzed [2 + 2 + 2] Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.8b02085

An original and mild synthetic route for the preparation of novel azafluorenones and derivatives via a ruthenium-mediated [2 + 2 + 2] cycloaddition of α,ω-diynes and cyanamides has been developed. This atom-economical catalytic process demonstrated remarkable regioselectivities to access fluorescent azafluorenone derivatives. The photophysical properties of azafluorenone derivatives have been evaluated, and photoluminescence phenomena at solid and liquid states have been highlighted.

Full text of DOI:10.1021/acs.orglett.8b02085

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Fluorescent Azafluorenones and Derivatives via a
Ruthenium-Catalyzed [2 + 2 + 2] Cycloaddition
Fei Ye,† Christine Tran,† Ludovic Jullien,‡ Thomas Le Saux,‡ Mansour Haddad,†
,†
Veronique Michelet,* and Virginie Ratovelomanana-Vidal*,†
́
†PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, Paris 75005, France
‡
́
́
PASTEUR, Chemistry Department, Ecole Normale Superieure, PSL University, Sorbonne University, CNRS, Paris 75005, France
S
* Supporting Information
ABSTRACT: An original and mild synthetic route for the preparation of novel azafluorenones and derivatives via a ruthenium-
mediated [2 + 2 + 2] cycloaddition of α,ω-diynes and cyanamides has been developed. This atom-economical catalytic process
demonstrated remarkable regioselectivities to access fluorescent azafluorenone derivatives. The photophysical properties of
azafluorenone derivatives have been evaluated, and photoluminescence phenomena at solid and liquid states have been
highlighted.
zafluorenones, azafluorenols, and related compounds serve
as privileged structures and constitute the central core of a
potential dual anti-tuberculosis and an anti-inflammatory drug
candidate.2c Furthermore, azafluorenones are also found in
some chromophores, although the properties and bioimaging
applications have rarely been reported. Recent investigations
demonstrated that aminoazafluorenones are potent, photo-
activatable fluorescent probes because of the effective
conjugative interaction of the nitrogen of the amino moiety
with the 14-π-electron indenopyridine system that could be used
for the lipid droplets (LDs)-specific live-cell imaging. 1-
Azafluorenone D was reported to be a nontoxic, highly selective,
and stable dye for staining LDs in different cell lines;3d 2-
azafluorenone E also presented typical aggregation-induced
emission (AIE) properties, compatible with LD in vitro imaging
(Figure 1).3e Given the crucial importance of azafluorenone
derivatives, the development of clean and flexible methods to
access azafluorenone derivatives efficiently is highly desirable.
Despite numerous strategies for the synthesis of azafluor-
enones,4 only a few examples have been reported for the
construction of aminoazafluorenones including amination
reactions,2c multicomponent heterocyclizations,3d,e oxidation
of 1,2-dihydroazafluorenones,2a and Pd-catalyzed autotandem
cyclizations.4i Alternatively, transition-metal-catalyzed [2 + 2 +
2] cycloaddition reactions are powerful methods to prepare
heteroaromatic compounds.5 More particularly, [2 + 2 + 2]
cycloadditions of alkynes with cyanamides have been extensively
explored to access 2-aminopyridine derivatives based on Co,6
Rh,7 Ni,8 Fe,9 Ir,10 and Ru,11,12f,g catalysis. As a continuation of
our recent investigations on transition-metal-catalyzed [2 + 2 +
A
variety of organic chemicals that have been found in natural
products and biologically active molecules.1 Among them,
aminoazafluorenones have received increasing interest in recent
years. Synthetic and natural aminoazafluorenones display
interesting properties and are present in a variety of
pharmacophores. As depicted in Figure 1, 3-amino-2-azafluor-
enone A is an antagonist of the adenosine A2a receptor,2a
piperazinyl-derived compound B exhibits an inhibitory effect on
topoisomerase as a potent anti-breast cancer candidate,2b and
isonicotinohydrazide derivative C has been evaluated as a
Received: July 3, 2018
Figure 1. Selected examples with azafluorenone units.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02085
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2] cyclization reactions,12 we hypothesized that novel
azafluorenone and azafluorenol derivatives could be accessed
through ruthenium-catalyzed [2 + 2 + 2] cycloadditions
(Scheme 1). To the best of our knowledge, such an approach
has not been reported so far.
Scheme 2. Ru-Catalyzed [2 + 2 + 2] Cycloaddition To Access
2-Azafluorenone and 3-Azafluorenone Derivatives
a
Scheme 1. Our Strategy for the Construction of
Azafluorenone(ol)s through [2 + 2 + 2] Cycloaddition
We initially studied the synthesis of 2-azafluorenones using
benzoyl-bridged 1,6-diynes containing a substituent on the
terminal position C1. The results are summarized in Scheme 2.
The benzoyl-bridged diyne 1a reacted with cyanamide 2a in the
presence of 2 mol % of Cp*Ru(CH3CN)3PF6 at room
temperature under solvent-free conditions, affording 3-amino-
2-azafluorenone 3a in 87% yield with excellent regioselectivity.
Screening different substituted cyanamides, such as morpholinyl
(2b), piperidinyl (2c), and N-methyl/N-benzyl derivatives (2d)
led to the desired 2-azafluorenones 3b−d in 78−92% yields with
regioselectivities of >99/1. Both electron-donating and electron-
withdrawing substituents, such as methoxy (1b) and fluoride
(1c), could be introduced to evaluate the influence of the phenyl
ring tether. Not only the alkyl groups, such as n-butyl and
cyclopropyl, but also aromatic groups are compatible on the
terminus of the diyne to deliver the corresponding cycloadducts
3i and 3j with high regioselectivities (for single-crystal X-ray
diffraction of 3i, see the Supporting Information). However,
TMS- and propenyl-substituted diynes (1d and 1e) provided
the corresponding products with low yields. Furthermore,
thienyl-based fluorenone 3k was obtained in 81% yield with
complete regioselectivity from thiophene-bridged diyne 1h and
pyrrolidine-1-carbonitrile 2a. In parallel to the synthesis of 2-
azafluorenones, exchanging the terminal position of the starting
diynes, such as 1i, allowed the formation of the 2-amino-3-
azafluorenone 4 in 89% yield with 94:6 regioselectivity. The
structure of the major product 4 was unambiguously confirmed
by single-crystal X-ray diffraction (see the SI).
Interestingly, we also found that the benzyl-bridged 1,6-
diynes containing a hydroxyl group were compatible with the
reaction conditions, affording the cycloadducts in good to high
yields with excellent regioselectivities (Scheme 3). Cyanamides
2a and 2b smoothly underwent the cycloaddition reactions to
provide the corresponding 6a and 6b in 81% and 68% yields,
respectively. Fluoride-substituted cycloadduct 6c was obtained
in 77% yield by using the corresponding diyne 5b. Functional
groups, such as TMS and propenyl, were all tolerated and gave
the functionalized 2-azafluorenols 6d and 6e in good yields.
Phenyl-substituted diynes 5e and 5f were successfully used in
the reaction to afford 6f and 6g in 73% and 53% yields,
respectively. Heteroaromatics, such as thienyl derivatives, were
amenable with the reaction conditions to produce the
corresponding product 6h in 87% yield. In addition to the
monosubstituted diynes, disubstituted diyne 5i containing a
a
Reaction conditions: 0.3−0.8 mmol of diyne 1, cyanamide 2 (2
equiv), and 2 or 5 mol % Cp*Ru(CH3CN)3PF6 were stirred in a
screw-capped tube under solvent-free conditions and an argon
atmosphere. Isolated yield. Regioselectivity was determined by
crude H NMR analysis. 1.2 equiv of 2 was used, and CH2Cl2 was
used as solvent. 1.2 equiv of 2 was used, DCE was used as solvent,
b
1
c
d
e
and the reaction was stirred at 80 °C. Conversion = 53%. 50 °C.
bromide could also be used to afford 1-bromo-2-azafluorenol 6i
in 69% yield with >99/1 regioselectivity. Similar to the synthesis
of 3-azafluorenone 4, but starting from 1,6-diynes 5h and 5j,
having substituents at position C7, the cyclizations furnished 3-
azafluorenols 7a and 7b in 71% and 78% yields, respectively,
with 99/1 regioselectivities.
Inspired by the efficient strategy to access azafluorenols
described in Scheme 3, the synthesis of a complex derivative 9
was then explored (Scheme 4). Tetrayne 8 was converted into
bis-azafluorenol 9 via a double Ru-catalyzed [2 + 2 + 2]
cycloaddition reaction in the presence of cyanamide 2a. The
expected product was obtained in 94% yield and >99/1
regioselectivity.
Azafluorenones and azafluorenols 3a−k, 6g, and 9 possess
attractive photophysical properties; these compounds exhibit
UV spectra with an absorption maxima (λmax) in the 380−450
B
DOI: 10.1021/acs.orglett.8b02085
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Synthesis of 2-Azafluorenols and 3-Azafluorenols
a
Reaction conditions: 0.3 or 0.5 mmol of diyne 5, cyanamide 2 (2 equiv), and 2 or 5 mol % of Cp*Ru(CH3CN)3PF6 were stirred in a screw-capped
b
1
tube under solvent-free conditions under an argon atmosphere. Isolated yield. Regioselectivity was determined by crude H NMR analysis. 1.2
equiv of 2 was used, and CH2Cl2 was used as solvent. 50 °C.
c
Scheme 4. Synthesis of Bis-azafluorenol Derivative 9
In conclusion, a straightforward unprecedented approach to
access azafluorenones is described. This strategy involves the
Ru-catalyzed [2 + 2 + 2] cycloaddition reaction of α,ω-diynes
and cyanamides, which efficiently and regioselectively allows the
construction of azafluorenone derivatives. An analogous method
was also studied for the synthesis of azafluorenols catalyzed with
Cp*Ru(CH3CN)3PF6. These results showed that the high
regioselectivities mainly relied on the steric hindrance of the
substituents on the terminus of the alkyne, which allowed the
formation of less sterically hindered regioisomers. Moreover,
photophysical properties of azafluorenones and some derivatives
demonstrated that these compounds exhibited photolumines-
cence in the solid and liquid states with significant fluorescence
quantum yields.
nm wavelength range and high molar absorption coefficients
(εmax) at λmax around 15000 M−1·cm−1 in acetonitrile at 293 K.
Additionally, all of these azafluorenones fluoresce in the 440−
570 nm wavelength range with quantum yields ranging from 0.1
to 0.5 (cf. the Supporting Information). Moreover, as depicted
in Figure 2 for 3b, photoluminescence was observed in the solid
state when these molecules were excited at 366 nm.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02085.
Experimental procedures, Analytical data, and NMR
spectra for all compounds are reported (PDF)
Accession Codes
CCDC 1850884−1850885 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Figure 2. Photoluminescence of 3b at 366 nm in MeCN and the solid
state.
*E-mail: veronique.michelet@unice.fr.
C
DOI: 10.1021/acs.orglett.8b02085
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2011, 40, 3430. (f) Hua, R.; Abrenica, M. V. A.; Wang, P. Curr. Org.
Chem. 2011, 15, 712. (g) Weding, N.; Hapke, M. Chem. Soc. Rev. 2011,
40, 4525. (h) Broere, D. L.; Ruijter, E. Synthesis 2012, 44, 2639.
(i) Tanaka, K. Heterocycles 2012, 85, 1017. (j) Wang, C.; Wan, B. Chin.
Sci. Bull. 2012, 57, 2338. (k) Okamoto, S.; Sugiyama, Y. Synlett 2013,
24, 1044. (l) Satoh, Y.; Obora, Y. Eur. J. Org. Chem. 2015, 2015, 5041.
*E-mail: virginie.vidal@chimie-paristech.fr.
ORCID
́
Veronique Michelet: 0000-0002-2217-9115
Virginie Ratovelomanana-Vidal: 0000-0003-1167-1195
Notes
̈
(m) Jungk, P.; Taufer, T.; Thiel, I.; Hapke, M. Synthesis 2016, 48, 2026.
The authors declare no competing financial interest.
(n) Babazadeh, M.; Soleimani-Amiri, S.; Vessally, E.; Hosseinian, A.;
Edjlali, L. RSC Adv. 2017, 7, 43716.
̈
(6) (a) Bonnemann, H.; Brijoux, W.; Brinkmann, R.; Meurers, W.
ACKNOWLEDGMENTS
This work was supported by the Ministere de l’Education
Nationale, de l’Enseignement Superieur et de la Recherche
(MENESR) and the Centre National de la Recherche
Scientifique (CNRS). We gratefully acknowledge the China
Scholarship Council (CSC) for a grant to F.Y. and warmly thank
Dr. M.-N. Rager (Chimie ParisTech, Paris) for 2D NMR
experiments and L.-M. Chamoreau and G. Gontard (IPCM,
■
Helv. Chim. Acta 1984, 67, 1616. (b) Heller, B.; Reihsig, J.; Schulz, W.;
Oehme, G. Appl. Organomet. Chem. 1993, 7, 641. (c) Fatland, A. W.;
Eaton, B. E. Org. Lett. 2000, 2, 3131. (d) Heller, B.; Sundermann, B.;
Buschmann, H.; Drexler, H.-J.; You, J.; Holzgrabe, U.; Heller, E.;
̀
́
Oehme, G. J. Org. Chem. 2002, 67, 4414. (e) Bon
H.-C.; Maryanoff, B. E. Chem. Commun. 2004, 2394. (f) Bon
R.; Zhang, H.-C.; Moretto, A. F.; Ye, H.; Gauthier, D. A.; Li, J.; Leo, G.
C.; Maryanoff, B. E. J. Am. Chem. Soc. 2005, 127, 3473. (g) Zhang, H.-
̃
aga, L. V. R.; Zhang,
̃
aga, L. V.
C.; Bonaga, L. V. R.; Ye, H.; Derian, C. K.; Damiano, B. P.; Maryanoff,
̃
́
Universite Pierre et Marie Curie, Paris) for X-ray analyses.
B. E. Bioorg. Med. Chem. Lett. 2007, 17, 2863. (h) Hapke, M.; Kral, K.;
Fischer, C.; Spannenberg, A.; Gutnov, A.; Redkin, D.; Heller, B. J. Org.
Chem. 2010, 75, 3993. (i) Nicolaus, N.; Schmalz, H.-G. Synlett 2010,
2010, 2071. (j) Garcia, P.; Evanno, Y.; George, P.; Sevrin, M.; Ricci, G.;
Malacria, M.; Aubert, C.; Gandon, V. Org. Lett. 2011, 13, 2030.
(k) Garcia, P.; Evanno, Y.; George, P.; Sevrin, M.; Ricci, G.; Malacria,
M.; Aubert, C.; Gandon, V. Chem. - Eur. J. 2012, 18, 4337.
REFERENCES
■
(1) (a) Koyama, J.; Morita, I.; Kobayashi, N.; Osakai, T.; Usuki, Y.;
Taniguchi, M. Bioorg. Med. Chem. Lett. 2005, 15, 1079. (b) Manpadi,
M.; Uglinskii, P. Y.; Rastogi, S. K.; Cotter, K. M.; Wong, Y.-S. C.;
Anderson, L. A.; Ortega, A. J.; Van Slambrouck, S.; Steelant, W. F. A.;
Rogelj, S.; Tongwa, P.; Antipin, M. Y.; Magedov, I. V.; Kornienko, A.
Org. Biomol. Chem. 2007, 5, 3865. (c) Mueller, D.; Davis, R. A.; Duffy,
S.; Avery, V. M.; Camp, D.; Quinn, R. J. J. Nat. Prod. 2009, 72, 1538.
(d) Prachayasittikul, S.; Manam, P.; Chinworrungsee, M.; Isarankura-
Na-Ayudhya, C.; Ruchirawat, S.; Prachayasittikul, V. Molecules 2009,
14, 4414. (e) Pumsalid, K.; Thaisuchat, H.; Loetchutinat, C.;
Nuntasaen, N.; Meepowpan, P.; Pompimon, W. Nat. Prod. Commun.
2010, 5, 1931. (f) Addla, D.; Sridhar, B.; Devi, A.; Kantevari, S. Bioorg.
Med. Chem. Lett. 2012, 22, 7475. (g) Banjerdpongchai, R.; Khaw-On,
P.; Ristee, C.; Pompimon, W. Asian Pacific. J. Cancer Prev. 2013, 14,
2637.
(7) Tanaka, K.; Suzuki, N.; Nishida, G. Eur. J. Org. Chem. 2006, 2006,
3917.
(8) (a) Kumar, P.; Prescher, S.; Louie, J. Angew. Chem., Int. Ed. 2011,
50, 10694. (b) Stolley, R. M.; Maczka, M. T.; Louie, J. Eur. J. Org. Chem.
2011, 2011, 3815. (c) Stolley, R. M.; Duong, H. A.; Louie, J.
Organometallics 2013, 32, 4952. (d) Zhong, Y.; Spahn, N. A.; Stolley, R.
M.; Nguyen, M. H.; Louie, J. Synlett 2015, 26, 307.
(9) (a) Lane, T. K.; D’ Souza, B. R.; Louie, J. J. Org. Chem. 2012, 77,
7555. (b) Wang, C.; Wang, D.; Xu, F.; Pan, B.; Wan, B. J. Org. Chem.
2013, 78, 3065. (c) Spahn, N. A.; Nguyen, M. H.; Renner, J.; Lane, T.
K.; Louie, J. J. Org. Chem. 2017, 82, 234.
(2) (a) Heintzelman, G. R.; Bullington, J. L.; Rupert, K. C. PCT Int.
Appl. WO 2005042500 A1, May 12, 2005. (b) Chen, T.-C.; Yu, D.-S.;
Chen, S.-J.; Chen, C.-L.; Lee, C.-C.; Hsieh, Y.-Y.; Chang, L.-C.; Guh, J.-
H.; Lin, J.-J.; Huang, H.-S. Arabian J. Chem. 2016, DOI: 10.1016/
j.arabjc.2016.06.014. (c) Tseng, C. H.; Tung, C. W.; Wu, C. H.; Tzeng,
C. C.; Chen, Y. H.; Hwang, T. L.; Chen, Y. L. Molecules 2017, 22, 1001.
(3) (a) Sharma, A.; Umar, S.; Kar, P.; Singh, K.; Sachdev, M.; Goel, A.
Analyst 2016, 141, 137. (b) Gao, M.; Su, H.; Lin, Y.; Ling, X.; Li, S.;
Qin, A.; Tang, B. Z. Chem. Sci. 2017, 8, 1763. (c) Landmesser, T.;
Linden, A.; Hansen, H.-J. Helv. Chim. Acta 2008, 91, 265. (d) Sharma,
A.; Umar, S.; Kar, P.; Singh, K.; Sachdev, M.; Goel, A. Analyst 2016,
141, 137. (e) Gao, M.; Su, H.; Lin, Y.; Ling, X.; Li, S.; Qin, A.; Tang, B.
Z. Chem. Sci. 2017, 8, 1763.
(10) (a) Hashimoto, T.; Ishii, S.; Yano, R.; Miura, H.; Sakata, K.;
Takeuchi, R. Adv. Synth. Catal. 2015, 357, 3901. (b) Takeuchi, R.;
Fujisawa, S.; Yoshida, Y.; Sagano, J.; Hashimoto, T.; Matsunami, A. J.
Org. Chem. 2018, 83, 1852.
(11) (a) Chowdhury, H.; Goswami, A. Adv. Synth. Catal. 2017, 359,
314. (b) Bhatt, D.; Patel, N.; Chowdhury, H.; Bharatam, P. V.;
Goswami, A. Adv. Synth. Catal. 2018, 360, 1876. (c) Yamamoto, Y.
Tetrahedron Lett. 2017, 58, 3787. (d) Chowdhury, H.; Goswami, A.
Org. Biomol. Chem. 2017, 15, 5824.
(12) (a) Auvinet, A.-L.; Ez-Zoubir, M.; Vitale, M. R.; Brown, J. A.;
Michelet, V.; Ratovelomanana-Vidal, V. ChemSusChem 2012, 5, 1888.
(b) Auvinet, A.-L.; Ez-Zoubir, M.; Bompard, S.; Vitale, M. R.; Brown, J.
A.; Michelet, V.; Ratovelomanana-Vidal, V. ChemCatChem 2013, 5,
2389. (c) Auvinet, A.-L.; Michelet, V.; Ratovelomanana-Vidal, V.
Synthesis 2013, 45, 2003. (d) Jacquet, J.; Auvinet, A.-L.; Mandadapu, A.
K.; Haddad, M.; Ratovelomanana-Vidal, V.; Michelet, V. Adv. Synth.
Catal. 2015, 357, 1387. (e) Ye, F.; Haddad, M.; Michelet, V.;
Ratovelomanana-Vidal, V. Org. Lett. 2016, 18, 5612. (f) Ye, F.; Haddad,
M.; Ratovelomanana-Vidal, V.; Michelet, V. Org. Lett. 2017, 19, 1104.
(g) Ye, F.; Haddad, M.; Michelet, V.; Ratovelomanana-Vidal, V. Org.
Chem. Front. 2017, 4, 1063. (h) Ye, F.; Boukattaya, F.; Haddad, M.;
Ratovelomanana-Vidal, V.; Michelet, V. New J. Chem. 2018, 42, 3222.
(4) (a) Kraus, G. A.; Kempema, A. J. Nat. Prod. 2010, 73, 1967.
(b) Dhara, S.; Ahmed, A.; Nandi, S.; Baitalik, S.; Ray, J. K. Tetrahedron
Lett. 2013, 54, 63. (c) Marquise, N.; Harford, P. J.; Chevallier, F.;
́
́
Roisnel, T.; Dorcet, V.; Gagez, A. L.; Sable, S.; Picot, L.; Thiery, V.;
Wheatley, A. E. H.; Gros, P. C.; Mongin, F. Tetrahedron 2013, 69,
10123. (d) Marquise, N.; Harford, P. J.; Chevallier, F.; Roisnel, T.;
Wheatley, A. E. H.; Gros, P. C.; Mongin, F. Tetrahedron Lett. 2013, 54,
3154. (e) Marquise, N.; Dorcet, V.; Chevallier, F.; Mongin, F. Org.
Biomol. Chem. 2014, 12, 8138. (f) Das, S.; Hong, D.; Chen, Z.-W.; She,
Z.-G.; Hersh, W. H.; Subramaniam, G.; Chen, Y. Org. Lett. 2015, 17,
5578. (g) Laha, J. K.; Jethava, K. P.; Patel, S. Org. Lett. 2015, 17, 5890.
(h) Zheng, M.; Chen, P.; Wu, W.; Jiang, H. Chem. Commun. 2016, 52,
́
́
84. (i) Marquise, N.; Chevallier, F.; Nassar, E.; Frederich, M.; Ledoux,
A.; Halauko, Y. S.; Ivashkevich, O. A.; Matulis, V. E.; Roisnel, T.;
Dorcet, V.; Mongin, F. Tetrahedron 2016, 72, 825. (j) Laha, J. K.;
Jethava, K. P.; Patel, S.; Patel, K. V. J. Org. Chem. 2017, 82, 76.
(5) For selected reviews, see: (a) Heller, B.; Hapke, M. Chem. Soc. Rev.
2007, 36, 1085. (b) Tanaka, K. Synlett 2007, 2007, 1977. (c) Varela, J.
́
A.; Saa, C. Synlett 2008, 2008, 2571. (d) Tanaka, K. Chem. - Asian J.
́
2009, 4, 508. (e) Domínguez, G.; Perez-Castells, J. Chem. Soc. Rev.
D
DOI: 10.1021/acs.orglett.8b02085
Org. Lett. XXXX, XXX, XXX−XXX