Gold-Catalyzed Synthesis of Tropone and Its Analogues via Oxidative Ring Expansion of Alkynyl Quinols

Article abstract of DOI:10.1021/acs.orglett.5b03160

A new and convenient strategy for the synthesis of functionalized tropone derivatives based on the gold-catalyzed oxidative ring expansion of alkynyl quinols has been developed. The reaction proceeds via gold-catalyzed highly regioselective oxidation foll

Full text of DOI:10.1021/acs.orglett.5b03160

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Synthesis of Tropone and Its Analogues via Oxidative
Ring Expansion of Alkynyl Quinols
Jidong Zhao, Jun Liu, Xin Xie, Shi Li,* and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: A new and convenient strategy for the synthesis of
functionalized tropone derivatives based on the gold-catalyzed
oxidative ring expansion of alkynyl quinols has been developed.
The reaction proceeds via gold-catalyzed highly regioselective
oxidation followed by 1,2-migration of a vinyl or phenyl group.
Extension of this chemistry allows ready access to various seven- or
six-membered ring systems such as benzotropones, benzooxepines,
phenanthrenes, and quinolin-2(1H)-ones.
ropones and their 2-hydroxylated derivative tropolones
constitute one of the most important nonbenzenoid seven-
membered aromatic compounds, and they have attracted
considerable interest due to their novel structures and their
presence in various natural products with biological interest.1 For
example, colchicine (Figure 1) is one of the most studied
Scheme 1. Synthesis of Tropones via Ring Expansion
Reactions
T
Figure 1. Representative naturally occurring bioactive tropone
derivatives.
tropolones, which was commonly used to treat acute gout,2
familial Mediterranean fever,3 and prophylaxis of gout flares. The
cage-like harringtonolide was found to possess antineoplastic and
antiviral activities.4 Theaflavic acid was found to display a variety
of important biological activities such as anti-inflammatory and
cytotoxic activities.5 Tropones have also been used as efficient
building blocks in a diverse array of higher order cycloaddition
reactions such as [4 + 2],6a [6 + 3],6b [6 + 4],6c [8 + 2],6d or [8 +
3]6e cyclizations leading to fused ring systems.6 Therefore, the
development of efficient methodologies for the synthesis of
tropone and its derivatives is highly attractive.1c,7−9
Among many approaches, ring expansion of six-membered
ring compounds via cyclopropanation/ring-expansion reactions
was the most often used protocol1c,8 (typical examples are shown
in Scheme 1, eq 1), which has been applied successfully to the
synthesis of tropone and tropolone-containing natural products.9
However, these reactions usually require multistep synthesis for
either the cyclopropanation precursors or the desired tropone
products, and in some cases, highly unstable reagents such as
diazo-compounds or dihalocarbenes need to be employed to
ensure efficient cyclopropanation. Recently, we have reported a
gold-catalyzed highly regio- and chemoselective oxidative ring
expansion10 of 2-alkynyl-1,2-dihydropyridines to azepines10a
using pyridine-N-oxide as the oxidant,11 which proceeds via
exclusive 1,2-migration of a vinyl or phenyl group. Inspired by
this result, we envisioned that an α-carbonyl gold carbenoid
intermediate B might be generated through the gold-catalyzed
oxidation of alkynyl quinols 1 bearing a tertiary propargyl alcohol
moiety, which may undergo ring expansion via 1,2-migration of
the vinyl group (pinacol type) to furnish the tropone derivatives.
It was noted that most of the gold-catalyzed reactions involving a
ring-enlargement process focused on the reactions of small-sized
ring compounds such as alkynyl-cyclopropanol or -cyclobutanols
Received: November 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
or were restricted to cycloalkanes,12 while the reactions of larger-
sized ring compounds, especially via the migration of a vinyl or
phenyl group from a carbocycle, were quite rare.13 Developing
such methodologies would allow the efficient synthesis of
medium- to large-sized carbo- and heterocycles, which is often a
challenge in organic synthesis. Herein, we report a new and
convenient strategy for the ring expansion of six-membered ring
compounds to functionalized tropones via the gold-catalyzed
oxidative rearrangement of alkynyl quinols (Scheme 1, eq 2),
which can be easily prepared with a one-step reaction from
readily accessible quinones via acetylide addition. In addition, the
method was also extended to the synthesis of various fused-ring
systems such as benzotropones, benzooxepines, phenanthrenes,
and quinolin-2(1H)-ones.
gold),15 however, the desired 3a was formed in a lower yield of
58% (Table 1, entry 6). The use of toluene or THF as the solvent
also afforded 3a in good yields of 78−88% (Table 1, entries 9−
10). Control experiments with PPh3AuCl or AgNTf2 alone did
not give the desired product (Table 1, entries 11−12). It should
be noted that the X-ray crystallographic analysis of 3a16 showed a
structure of 2-benzoyl-5-hydroxy tropone (3a′). However,
HMBC experiments of 3a and other related products in
CDCl3 indicated that the hydroxyl group is close to the
phenylcarbonyl group (structure of 3a). Moreover, protection
of 3a afforded a mixture of 4a16 and 5a (Scheme 2). Thus, it is
Scheme 2. Protection of 3a
To study the feasibility of the hypothesis, we initially
investigated the gold-catalyzed oxidative reaction of alkynyl
quinol 1a with a phenyl substituent at the alkyne terminus (Table
1). To our delight, the desired tropone product 3a was formed
Table 1. Optimization Studies for the Formation of 3a
likely that, in solution, tropone 3a equilibrates with 3a′, in which
3a is the dominant species due to exhibiting intramolecular H-
bonding. However, the equilibrium can shift to 3a′ in different
solvents or under certain conditions. 3a′ predominates in its solid
form, possibly caused by the intermolecular H-bonding.
Next, the substrate scope of this ring-expansion reaction was
evaluated under the reaction conditions shown in Table 1, entry
1. As shown in Scheme 3, a wide range of diversely substituted
Scheme 3. Gold-Catalyzed Ring Expansion of Alkynyl Quinols
to Tropones
a
a
entry N-oxide
catalyst
solvent
time (h) yield (%)
1
2a
2a
2a
2a
2a
2a
2b
2c
2a
2a
2a
2a
PPh3AuNTf2
PPh3AuCl/AgOTf
PPh3AuCl/AgSbF6
PPh3AuCl/AgBF4
PPh3AuCl/AgPF6
PicAuCl2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
THF
DCE
DCE
2
4
91
2
83
3
4
91
4
4
84
5
4
85
6
12
24
6
58
7
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuCl
70
8
40
9
4
88
10
11
12
4
78
6
0 (98)
0 (89)
AgNTf2
12
a
Isolated yields. The yields of the recovered 1a are shown in
parentheses.
quantitatively at room temperature within hours upon treatment
of 1a with 5 mol % of PPh3AuNTf2 and 1.2 equiv of 8-
methylquinoline N-oxide in DCE. However, the NMR analysis of
3a indicated that it contained a trace amount of impurity, which
was difficult to remove by column chromatography. In view of
the acidic property of tropone 3a due to the presence of an enolic
hydroxyl group,14 we found that 3a could be obtained in high
purity and also with a high yield of 91% by treatment of the
reaction mixture with 0.5 M NaOH aqueous solution followed by
acidification and subsequent column chromatography (Table 1,
entry 1). Further screening of the catalysts and reaction
conditions revealed that changing the counterions on the gold
a
Isolated yields. All reactions were carried out on 0.3 mmol scale.
aryl and alkyl alkynes were suitable for this reaction, and the
desired tropones 3a−3l were obtained in good to excellent yields
within a short reaction time.17 Both of the electron-deficient (p-
F, p-Cl, p-CF3) and electron-rich substituents (p-Me, p-OMe,
3,4,5-(MeO)3) on the aryl rings were tolerated well during the
reaction, leading to 3b−3g in 66−91% yields. The results
indicated that, in general, the electronic nature of the aryl
substituents had some influence on the product yields. A
heteroaryl-substituted alkyne such as thienyl-substituted one was
also compatible in this reaction, furnishing 3h in 87% yield. The
catalysts to OTf−, SbF6 , BF4 , or PF6 only have a slight
influence on the reaction course, as 3a was obtained in 83−91%
yields in these cases (Table 1, entries 2−5). In the presence of
gold(III) complex PicAuCl2 (dichloro(2-pyridinecarboxylato)-
−
−
−
B
DOI: 10.1021/acs.orglett.5b03160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactions also proceeded smoothly with the alkyl-substituted
alkynes. For example, a linear alkyl group such as n-butyl- or
phenylethyl-substituted alkynes provided 3i and 3j in 88% and
77% yields, respectively. An alkyne with a methyl-protected
alcohol moiety was transformed into 3k in a satisfactory yield of
61%. A cyclopropyl substituted alkyne was also well tolerated,
furnishing 3l in 78% yield, while the cyclopropane ring remained
intact.
Encouraged by these results, we next anticipated that a broad
range of substrates with different structural features could
undergo ring expansion with comparable efficiency. In principle,
any appropriate cyclic compounds bearing a propargyl alcohol
moiety could be suitable substrates for the construction of new
carbo- or heterocycles with one-carbon ring expansion by this
chemistry. The representative results are shown in Table 2. Our
tropone as a mixture of two regioisomers. The predominant
product in this reaction was ketone 9 via 1,2-vinyl migration,
indicating that the migratory aptitude of a vinyl group is more
favorable than a phenyl group. Major isomer 9 possibly also
forms an equilibrium with its tautomer similar to that of 3 and 3′,
although the 2D NMR spectra (HMBC) indicated that the OH
group is close to the phenylcarbonyl group. Ring expansion of 11
derived from anthracene-9,10-dione proceeded quite efficiently
in the presence of simple pyridine N-oxide as the oxidant,
furnishing dibenzotropone 12 in 93% yield. Similar ring
expansion was also observed in the reaction of 13, in which the
carbonyl group had been replaced by an oxygen atom. The
corresponding benzooxepine 14 was formed with a lower yield of
39%. Substrate 15 derived from 9-fluorenone underwent the
ring-expansion reaction efficiently to produce 9-hydroxy-
phenanthrene 16 in a high yield of 97%. Alkyne 17 derived
from isatin was also a perfect substrate for this ring-expansion
reaction, leading to 3-hydroxy-quinolin-2(1H)-one derivative 18
via a selective 1,2-phenyl migration in 82% yield, while a product
derived from a 1,2-carbonyl migration was not detected. 3-
Hydroxy-quinolinones are present in a variety of biologically
active substances or natural products,18 which are usually
prepared by ring expansion of diazo adducts of isatins.19 Our
method could avoid the use of the hazardous diazo compounds.
The results in Table 2 indicate that the current method can be a
general and attractive approach for the synthesis of a diverse type
of carbo- or heterocycles, especially for medium-sized ring
compounds which are difficult to access. The structures of the
obtained products were further confirmed by X-ray crystallo-
graphic analyses of 7c, 7e, 10, 12, and 18.16 It was noted that
most of the products listed in Table 2 can be purified directly by
column chromatography on silica gel.
Table 2. Gold-Catalyzed Ring Expansion of Various Carbo- or
Heterocycles
In the absence of N-oxide, a diketone product 21 was obtained
in 40% yield, along with 17% of 4-(phenylethynyl)phenol 22
(Scheme 4). The results were in complete contrast with Pt-
Scheme 4. Formation of Diketone 21
a
b
catalyzed reactions of alkynyl quinols, in which a 1,2-alkynyl
migration followed by cyclization occurs to afford 5-hydroxy-
benzofurans.20 The formation of 21 might be rationalized by first
generating enone 19 via gold-catalyzed Meyer−Schuster
rearrangement21 of 1a with water contaminated in the reaction
mixture followed by conjugate addition and oxidation. Addition
of 1 equiv of water could accelerate the reaction (3 h), however,
producing the same yield of 21 (40%). 18O-isotope labeling
experiments with H218O indicated that both of the carbonyl
oxygens were labeled, which supported the proposed mecha-
nism.
In summary, we have developed a new and convenient strategy
for the synthesis of functionalized tropones based on the gold-
catalyzed oxidative ring expansion of alkynyl quinols. The
reaction proceeds via a gold-catalyzed highly regioselective
oxidation followed by the 1,2-migration of a vinyl or phenyl
group. Extension of this chemistry allows ready access to various
Isolated yields. Pyridine N-oxide was used.
initial results of gold-catalyzed ring expansion of alkynyl quinol
derivatives with a MeO− substituent at the C-4 position were
very promising, leading to tropones 7a−7c in 84−89% yields.
Alkoxy, alkyl, and aryl groups as R substituents were all
compatible in these reactions. The results also revealed that
further elimination of a methoxy group occurred during the
process, possibly, assisted by a gold catalyst. In the case of 6d
functionalized with a chlorine substituent, selective migration of
the alkenyl moiety bearing no substituent occurred to give 7d
exclusively in 73% yield, indicating a more nucleophilic alkene
side migrated preferentially. The steric effect of the chlorine
group may also account for the selectivity. Regioselective
migration of the nonsubstituted vinyl group was also observed
in furanyl-substituted 6e, possibly due to steric hinderance.
Alkyne 8 derived from 1,4-naphthoquinone afforded benzo-
C
DOI: 10.1021/acs.orglett.5b03160
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
5813. (d) Roberts, V. A.; Garst, M. E.; Torres, N. E. J. Org. Chem. 1984,
49, 1136. (e) Banwell, M. G.; Collis, M. P. J. Chem. Soc., Chem. Commun.
1991, 1343. (f) Banwell, M. G.; Collis, M. P.; Mackay, M. F.; Richards, S.
L. J. Chem. Soc., Perkin Trans. 1 1993, 1913. (g) Dastan, A.; Saracoglu,
N.; Balci, M. Eur. J. Org. Chem. 2001, 2001, 3519.
(9) (a) Frey, B.; Wells, A. P.; Rogers, D. H.; Mander, L. N. J. Am. Chem.
Soc. 1998, 120, 1914. (b) Hong, S.-K.; Kim, H.; Seo, Y.; Lee, S. H.; Cha,
J. K.; Kim, Y. G. Org. Lett. 2010, 12, 3954.
(10) (a) Chen, M.; Chen, Y.; Sun, N.; Zhao, J.; Liu, Y.; Li, Y. Angew.
Chem., Int. Ed. 2015, 54, 1200. (b) For a related paper, see: Chen, M.;
Sun, N.; Xu, W.; Zhao, J.; Wang, G.; Liu, Y. Chem.Eur. J., DOI:
10.1002/chem.201504165 (Web released).
seven- or six-membered ring systems such as benzotropones,
benzooxepines, phenanthrenes, and quinolin-2(1H)-ones. These
results demonstrate the great synthetic utility of this method-
ology. Further applications of this chemistry toward highly
valuable carbo- or heterocycles are in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03160.
Experimental details, spectroscopic characterization of all
new compounds (PDF)
(11) For gold-catalyzed reactions using pyridine or quinoline N-oxides
as the oxidants, for a review, see: (a) Zhang, L. Acc. Chem. Res. 2014, 47,
877. For selected papers, see: (b) Ye, L.; He, W.; Zhang, L. J. Am. Chem.
Soc. 2010, 132, 8550. (c) Vasu, D.; Hung, H. H.; Bhunia, S.; Gawade, S.
A.; Das, A.; Liu, R. S. Angew. Chem., Int. Ed. 2011, 50, 6911. (d) Luo, Y.;
Ji, K.; Li, Y.; Zhang, L. J. Am. Chem. Soc. 2012, 134, 17412. (e) Wang, L.;
Xie, X.; Liu, Y. Angew. Chem., Int. Ed. 2013, 52, 13302. (f) Henrion, G.;
Chavas, T. E. J.; Le Goff, X.; Gagosz, F. Angew. Chem., Int. Ed. 2013, 52,
X-ray crystallography of 3a′ (CIF)
X-ray crystallography of 3e′ (CIF)
X-ray crystallography of 4a (CIF)
X-ray crystallography of 7c (CIF)
X-ray crystallography of 7e (CIF)
X-ray crystallography of 10 (CIF)
X-ray crystallography of 12 (CIF)
X-ray crystallography of 18 (CIF)
6277. (g) Nosel, P.; dos Santos Comprido, L. N.; Lauterbach, T.;
̈
Rudolph, M.; Rominger, F.; Hashmi, A. S. K. J. Am. Chem. Soc. 2013,
135, 15662. (h) Sun, N.; Chen, M.; Liu, Y. J. Org. Chem. 2014, 79, 4055.
̌
̌ ́ ́
(i) Schulz, J.; Jasíkova, L.; Skríba, A.; Roithova, J. J. Am. Chem. Soc. 2014,
136, 11513. (j) Wang, T.; Shi, S.; Hansmann, M. M.; Rettenmeier, E.;
Rudolph, M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2014, 53, 3715.
(k) Wang, T.; Shi, S.; Rudolph, M.; Hashmi, A. S. K. Adv. Synth. Catal.
2014, 356, 2337. (l) Wang, T.; Huang, L.; Shi, S.; Rudolph, M.; Hashmi,
A. S. K. Chem. - Eur. J. 2014, 20, 14868.
(12) For a review, see: (a) Garayalde, D.; Nevado, C. Beilstein J. Org.
Chem. 2011, 7, 767. For recent papers, see: (b) Luzung, M. R.;
Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858.
(c) Markham, J. P.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 9708. (d) Li, G.; Zhang, L. Angew. Chem., Int. Ed. 2007, 46, 5156.
(e) Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 9178.
(f) Hashmi, A. S. K.; Wang, T.; Shi, S.; Rudolph, M. J. Org. Chem. 2012,
77, 7761. (g) Gronnier, C.; Boissonnat, G.; Gagosz, F. Org. Lett. 2013,
15, 4234. (h) Shu, X.-Z.; Zhang, M.; He, Y.; Frei, H.; Toste, F. D. J. Am.
Chem. Soc. 2014, 136, 5844.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: lishi006@sioc.ac.cn.
*E-mail: yhliu@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Grant Nos. 21125210, 21421091, 21372244, 21572256) and
Chinese Academy of Science for financial support. We also thank
Mr. Jiayuan Li of Lanzhou University for his effort on the
optimization of the purification process.
(13) For a report involving migration of an alkenyl group within a
carbocycle as a side reaction, see: Yeom, H.-S.; Lee, Y.; Jeong, J.; So, E.;
Hwang, S.; Lee, J.-E.; Lee, S. S.; Shin, S. Angew. Chem., Int. Ed. 2010, 49,
1611.
REFERENCES
■
(1) For reviews, see: (a) Fischer, G. Adv. Heterocycl. Chem. 1996, 66,
285. (b) Zhao, J. Curr. Med. Chem. 2007, 14, 2597. (c) Liu, N.; Song, W.;
Schienebeck, C. M.; Zhang, M.; Tang, W. Tetrahedron 2014, 70, 9281.
(2) Terkeltaub, R. A. N. Engl. J. Med. 2003, 349, 1647.
(3) Drenth, J. P. H.; van der Meer, J. W. M. N. Engl. J. Med. 2001, 345,
1748.
(4) Kang, S. Q.; Cai, S. Y.; Teng, L. Acta Pharmacol. Sin. 1981, 16, 867.
(5) Sang, S.; Lambert, J. D.; Tian, S.; Hong, J.; Hou, Z.; Ryu, J.-H.;
Stark, R. E.; Rosen, R. T.; Huang, M.-T.; Yang, C. S.; Ho, C.-T. Bioorg.
Med. Chem. 2004, 12, 459.
(14) The 1H NMR analysis of the reaction mixture indicated that the
hydroxyl proton of 3a was absent, possibly due to the existence of basic
species such as 8-methylquinoline in the reaction mixture, which
captured this acidic proton.
(15) Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.; Kurpejovic,
́
E.
Angew. Chem., Int. Ed. 2004, 43, 6545.
(16) The X-ray crystallography of 3a′, 3e′, 4a, 7c, 7e, 10, 12, and 18 are
shown in the Supporting Information.
(17) TsOH·H2O was required as an additive to complete the reaction
when the reaction was scaled up; for details, see the Supporting
Information.
(18) (a) Sagong, H. Y.; Parhi, A.; Bauman, J. D.; Patel, D.; Vijayan, R. S.
K.; Das, K.; Arnold, E.; LaVoie, E. J. ACS Med. Chem. Lett. 2013, 4, 547.
(b) Wei, M.-Y.; Yang, R.-Y.; Shao, C.-L.; Wang, C.-Y.; Deng, D.-S.; She,
Z.-G.; Lin, Y.-C. Chem. Nat. Compd. 2011, 47, 322.
(19) Gioiello, A.; Venturoni, F.; Marinozzi, M.; Natalini, B.; Pellicciari,
R. J. Org. Chem. 2011, 76, 7431.
(6) (a) Li, P.; Yamamoto, H. J. Am. Chem. Soc. 2009, 131, 16628.
(b) Trost, B. M.; McDougall, P. J.; Hartmann, O.; Wathen, P. T. J. Am.
Chem. Soc. 2008, 130, 14960. (c) Ashenhurst, J. A.; Isakovic, L.; Gleason,
J. L. Tetrahedron 2010, 66, 368. (d) Xie, M.; Liu, X.; Wu, X.; Cai, Y.; Lin,
L.; Feng, X. Angew. Chem., Int. Ed. 2013, 52, 5604. (e) Rivero, A. R.;
́
́
Fernandez, I.; Sierra, M. A. Org. Lett. 2013, 15, 4928.
(7) For a review, see: (a) Banwell, M. G. Aust. J. Chem. 1991, 44, 1. For
recent papers, see: (b) Nair, V.; Sethumadhavan, D.; Nair, S. M.; Rath,
N. P.; Eigendorf, G. K. J. Org. Chem. 2002, 67, 7533. (c) Do, Y.-S.; Sun,
R.; Kim, H. J.; Yeo, J. E.; Bae, S.-H.; Koo, S. J. Org. Chem. 2009, 74, 917.
(d) Williams, Y. D.; Meck, C.; Mohd, N.; Murelli, R. P. J. Org. Chem.
2013, 78, 11707. (e) Harris, R. J.; Widenhoefer, R. A. Angew. Chem., Int.
Ed. 2014, 53, 9369. (f) Shirke, R. P.; Ramasastry, S. S. V. J. Org. Chem.
2015, 80, 4893.
(20) Kim, I.; Kim, K.; Choi, J. J. Org. Chem. 2009, 74, 8492.
(21) (a) Pennell, M. N.; Turner, P. G.; Sheppard, T. D. Chem. - Eur. J.
2012, 18, 4748. (b) Hansmann, M. M.; Hashmi, A. S. K.; Lautens, M.
Org. Lett. 2013, 15, 3226. (c) Yu, Y.; Yang, W.; Pflasterer, D.; Hashmi, A.
̈
S. K. Angew. Chem., Int. Ed. 2014, 53, 1144.
(8) (a) Bartels-Keith, J. R.; Johnson, A. W.; Taylor, W. I. J. Chem. Soc.
1951, 2352. (b) Macdonald, T. L. J. Org. Chem. 1978, 43, 3621.
(c) Evans, D. A.; Tanis, S. P.; Hart, D. J. J. Am. Chem. Soc. 1981, 103,
D
DOI: 10.1021/acs.orglett.5b03160
Org. Lett. XXXX, XXX, XXX−XXX