Asymmetric Construction of 2,3-Dihydroisoxazoles via an Organocatalytic Formal [3 + 2] Cycloaddition of Enynes with N-Hydroxylamines

Article abstract of DOI:10.1021/acs.orglett.6b01737

An organocatalytic asymmetric formal [3 + 2] cycloaddition of enynones with N-hydroxylamines has been described. A newly designed multifunctional organocatalyst was found to be highly effective, and the method allowed the synthesis of a variety of 2,3-dih

Full text of DOI:10.1021/acs.orglett.6b01737

Letter
pubs.acs.org/OrgLett
Asymmetric Construction of 2,3-Dihydroisoxazoles via an
Organocatalytic Formal [3 + 2] Cycloaddition of Enynes with
N‑Hydroxylamines
Wenbo Li, Xiuzhao Yu, Zhenting Yue, and Junliang Zhang*
†
†
†
,†,‡
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, China
‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, China
*
S Supporting Information
ABSTRACT: An organocatalytic asymmetric formal [3 + 2]
cycloaddition of enynones with N-hydroxylamines has been
described. A newly designed multifunctional organocatalyst
was found to be highly effective, and the method allowed the
synthesis of a variety of 2,3-dihydroisoxazoles in good yields
with excellent enantioselectivity.
7
2
,3-Dihydroisoxazoles (4-isoxazolines) are a fundamental
through an iminium activation pathway (Scheme 1b).
structural class in organic chemistry where they have served as
Undoubtedly, with the significance of enantioenriched 2,3-
dihydroisoxazoles, the development of a novel and efficient
process is still highly desirable.
1
useful synthetic intermediates. This structure can be found in
2
various biologically active compounds and natural products.
Considerable research efforts have been directed toward the
development of synthetic methods for 2,3-dihydroisoxazoles, but
their construction in a catalytic enantioselective manner is still a
Over the past decade, with the rapid development of
organocatalysis, cinchona alkaloids and their derivatives have8
been successfully applied in many enantioselective reactions.
Deng discovered that cinchona alkaloid derivatives bearing a free
hydroxyl group at the 6′-position of the quinoline are especially
3
rather challenging subject in asymmetric synthesis. The
significance of these chiral 2,3-dihydroisoxazole motifs has led
to the demand for efficient synthetic methods, and some progress
has been made. For example, Ukaji, Inomata, and co-workers
developed an asymmetric addition of alkynylzinc reagents to
nitrones utilizing di-tert-butyl (R,R)-tartrate as a chiral auxiliary
to afford the corresponding optically active propargyl hydroxyl-
amines, and subsequent cyclization would produce the
9
effective. Recent research efforts directed at modifying the H-
bond donor of naturally occurring cinchona alkaloids (C9-OH),
which can be advantageously exploited to fine-tune properties
such as basicity and conformation, have led to the identification
of more enantioselective and general catalysts for the
10
enantioselective transformations. While catalytic asymmetric
4
corresponding enantioenriched 2,3-dihydroisoxazoles. One of
conjugate additions to a carbon−carbon double bond with
11
cinchona alkaloid-derived catalysts are well-established, reports
of stereocontrolled Michael addition reactions of α,β-disub-
stituted systems are scarce. During our ongoing investigation on
base-catalyzed tandem reaction of electron-deficient 1,3-
the most attractive approaches to the enantioselective synthesis
of 4-isoxazolines is asymmetric metal- or organocatalyst-
catalyzed 1,3-diplolar cycloaddition of nitrones to acetylenes.
For example, Ishihara and co-workers reported a highly
enantioselective dipolar [3 + 2] cycloaddition of acetylenic
derivatives, propioloylpyrazoles, with nitrones using a chira5l
copper complex to produce a set of chiral 2,3-dihydroisoxazoles.
Enantioselective methods employing organocatalytic approaches
are more rarely reported. Recently, Sun and co-workers disclosed
the first organocatalytic asymmetric dipolar [3 + 2] cycloaddition
between acetylenic aldehydes and nitrones that are in situ formed
12
12a
conjugated enynes with hydroxylamines, we report herein
an asymmetric formal [3 + 2] cycloaddition of enynones with
hydroxylamines to furnish a series of highly substituted 2,3-
dihydroisoxazoles in good yields and high ee values using a new
organocatalyst derived from cinchona alkaloids (Scheme 1c).
In initial attempts, the formal [3 + 2] cycloaddition of enynone
1a with N-benzylhydroxylamine 2a in the presence of 10 mol %
of quinine was carried out in toluene at room temperature for 16
from N-alkylhydroxylamines and aldehydes in one pot (Scheme
6
1
a). Meanwhile, the Aleman
́
group devoted their independent
efforts to the development of the organocatalytic enantiose-
Received: June 15, 2016
lective 1,3-dipolar cycloadditions of alkynals with nitrones
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01737
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Organocatalytic Access to Chiral 2,3-
Dihydroisoxazoles
cinchona alkaloids (Figure 1, 3a−d). It is noteworthy that the
catalyst 3c with a 2-pyridinyl substituent displayed substantially
Figure 1. Screened organocatalysts.
higher reactivity in this transformation (Table 1, entry 5). When
C6′-OH of catalyst 3c was changed to C6′-OMe of catalyst 3e,
the cycloaddition delivered only a trace amount of the [3 + 2]
annulation product (Table 1, entry 7), indicating that C6′-OH
plays a crucial role for the activity. Meanwhile, the catalyst 3f with
the dual H-bond component displayed similar reactivity but
significantly lower enantioselectivity relative to catalyst 3a (Table
1
, entry 8). Further modification of the catalyst structure with
introduction of an ester group on the C9 substituent had a
pronounced beneficial effect on the enantioselectivity. Catalysts
3g and 3h afforded the product in very good enantioselectivity
but with low yields (Table 1, entries 9 and 10). Catalyst 3i, which
bears a pyridinyl group on the ester moiety, attained a higher
yield with 91% ee in shorter time (Table 1, entries 11 vs 9 and
h to give 2,3-dihydroisoxazole 4aa in 88% yield with an
enantiomeric excess (ee) of 33% (Table 1, entry 1). The
cycloaddition of 1a and 2a with QD (QD = quinidine) delivered
the 4aa in 59% ee (Table 1, entry 2). We then screened various
13,14
a
1
0).
Interestingly, the use of 3j or 3k as catalysts with an N-
Table 1. Optimization of the Reaction Conditions
methylimidazole group or a 2-quinoline group also gave
moderate yield and good ee (Table 1, entries 12 and 17). In
addition, catalyst 3l with an indole moiety could give good ee but
low catalytic activity (Table 1, entry 18). The solvent effect was
then examined, and no better result could be obtained (Table 1,
entries 13−16). These results imply that the multifunctionality
consisting of an ester group, the basic heterocycle (pyridine,
imidazole, and quinoline), and a hydroxyl group is crucial for
catalytic activity and enantioselectivity. On the basis of the ee
values of the products, catalysts 3i−k (Figure 1) were selected for
further investigation.
b
c
entry
catalyst
solvent
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
quinine
QD
3a
3b
3c
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH Cl
16
17
18
16
2
88
81
33
59
77
73
56
63
81
98
72
With optimized reaction conditions in hand, we evaluated this
methodology with various N-substituted hydroxylamines 2
3d
3e
3f
9
72
120
5.5
120
120
20
16
10
10
20
20
14
72
trace
90
(
Scheme 2). The N-(naphthalen-1-ylmethyl)hydroxylamine 2b
59
89
94
91
90
85
87
87
83
92
87
smoothly underwent the asymmetric cycloaddition to furnish the
corresponding cyclic product 4ab in 52% yield with 93% ee.
Additionally, sterically hindered N-(anthracen-9-ylmethyl)-
hydroxylamine 2c gave cycloadduct 4ac in 66% yield and 91%
ee. A range of N-(2-aryl)hydroxylamines (2d−g) bearing either
electron-deficient or -rich aryl substituents underwent the
tandem reactions smoothly to afford the desired products
3g
3h
3i
12
10
11
12
13
14
15
16
17
18
22
53
3j
58
3j
55
2
2
3j
DCE
55
3j
xylene
43
4ad−ag in 33−72% yields with 83−99% ee. By increasing the
3j
Ph−Cl
toluene
toluene
60
catalyst loading of 3k to 15 mol %, the reaction of 1a with 2g gave
the corresponding product 4ag in 72% yield and 94% ee. As for
N-(2-methoxybenzyl)hydroxylamine 2f and N-benzhydrylhy-
droxylamine 2h, the reactions resulted in low yields but excellent
enantioselectivity (4af, 33%, 99% ee; 4ah, 30%, 99% ee).
Remarkably, the hydroxylamine 2i bearing a furan-2-yl group
3k
3l
50
31
a
The reaction was conducted with 1a (0.2 mmol) and 2a (0.26 mmol)
in solvent (5 mL) at 23 °C in the presence of catalyst. Isolated yield.
b
c
The ee value was determined by chiral HPLC.
B
DOI: 10.1021/acs.orglett.6b01737
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Organocatalytic Access to Chiral 2,3-
Dihydroisoxazoles
Table 2. Substrate Scope of Enynones
1
2
3
entry
R /R /R (1)
time (h) 4, yield (ee) (%)
1
2
3
4
5
6
7
8
9
Ph/4-ClC H /Me (1b)
36
22
10
39
34
20
10
10
20
13
9
4bg, 89 (89)
4cg, 83 (89)
4dg, 90 (90)
4eg, 62 (93)
4fg, 67 (90)
4gg, 83 (91)
4hg, 62 (87)
4ig, 81 (91)
4jg, 79 (87)
4kg, 53 (94)
4lg, 75 (90)
4mg, 67 (93)
4ng, 64 (90)
4og, 54 (90)
4pg, 54 (63)
4qg, 77 (83)
6
4
Ph/4-CF C H /Me (1c)
3
6
4
4-NO C H /Ph/Me (1d)
2
6
4
4-FC H /Ph/Me (1e)
6
4
4-ClC H /Ph/Me (1f)
6
4
4-BrC H /Ph/Me (1g)
6
4
4-HOCC H /Ph/Me (1h)
6
4
4-MeOCC H /Ph/Me (1i)
6
4
4-MeO CC H /Ph/Me (1j)
2
6
4
10
11
12
13
14
15
16
Th/Ph/Me (1k)
4-MeO CC H /4-MeOC H /Me (1l)
2
6
4
6
4
4-BrC H /4-MeOC H /Me (1m)
64
64
72
34
10
6
4
6
4
4-MeC H /4-ClC H /Me (1n)
6
4
6
4
4-MeOC H /4-CF C H /Me (1o)
6
4
3
6
4
Ph/Ph/Ph (1p)
Ph/Ph/4-ClC H (1q)
6
4
a
The reaction was conducted with 1 (0.2 mmol) and 2g (0.26 mmol)
in toluene (5 mL) at room temperature in the presence of catalyst 3k
15 mol %). Yield of the isolated product after column
(
chromatography. The ee value was determined by chiral HPLC.
a
b
Catalyst 3i (15 mol %), 2e (0.3 mmol). Catalyst 3k (15 mol %).
obtained product 4gg to give the corresponding alcohol 5 with
excellent diastereoselectivities and good yields, maintaining the
enantiomeric excess of the starting ketone (eq 1).
worked well in the presence of catalyst 3j to provide the product
4
ai in 61% yield with 91% ee.
To further investigate the substrate scope of the present
catalytic system, we performed the catalytic asymmetric formal
3 + 2] cycloaddition with a range of enynones using 3k as the
[
catalyst (Table 2). In general, electron-deficient conjugated
enynes favored this process. Reactions of various enynes
containing electron-rich or electron-deficient aryl groups on
2
the alkenyl moiety (R ) with 2g afforded the corresponding 2,3-
dihydroisoxazoles in good yields with excellent enantioselectiv-
ities (4bg−cg, 4lg−og: 54−89% yield, 89−93% ee) (entries 1, 2,
and 11−14). It should be noted that the reaction required a
longer time for achieving full conversion when the substrate
contained electron-donating groups. To our delight, the
12
On the basis of our previous work, the plausible mechanism
of this multifunctional organocatalyst-catalyzed cycloaddition
reaction is proposed in Figure 2. The Michael donor was
substrate 1d with a nitrophenyl group on the alkyne moiety
1
(
R ) could deliver 4dg in 90% yield and 90% ee (entry 3).
Various enynes (1e−g) with halogen substituents reacted
successfully under the optimized conditions (4eg−gg: 62−83%
yield, 90−93% ee) (entries 4−6). Furthermore, different
electron-withdrawing groups on the aromatic ring of the alkyne
1
moiety (R ), such as aldehyde, ketone, and ester substituents,
were well compatible, providing the desired products in 62−81%
yields and 87−91% ee (entries 7−9). Gratifyingly, substrate 1k
1
with a 2-thienyl substituent on the alkyne moiety (R ) treated
with 2g afforded the cycloaddition product 4kg in 94% ee (entry
1
0). In the case of 1p and 1q bearing an aryl substituent on the
ketone moiety, the reaction was successfully performed, giving
highly substituted 2,3-dihydroisoxazoles 4pg and 4qg in
moderate yield and good ee (entries 15 and 16). The absolute
configuration of adduct 4ag, generated from reaction of enynone
1
a and hydroxylamine 2g, was determined by X-ray crystallog-
15
raphy. Furthermore, the use of NaBH enabled reduction of
Figure 2. Plausible mechanism.
4
C
DOI: 10.1021/acs.orglett.6b01737
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
activated through the quinuclidine amine function and the N-
hetaryl substituents on a C-9 ester, and the Michael acceptor was
associated with the quinoline phenol through a developing
hydrogen bond. The enantioselective nucleophilic addition
takes place via a concerted hydrogen transfer. Then the chiral
base captures another proton of the hydrozylamine to give
oxygen anion III. After nucleophilic attack of the oxygen anion to
the allenyl ketone intermediate III, transition state IV forms and
subsequent protonation affords product 4.
In summary, we have developed a facile asymmetric formal
cycloaddition of electron-deficient 1,3-enynes and N-hydroxyl-
amines. The newly designed organocatalysts derived from
cinchona alkaloids were demonstrated as optimal catalytic
systems for inducing asymmetry in the synthesis of highly
substituted 2,3-dihydroisoxazoles in high yields (up to 90%) with
excellent enantioselectivities (ee up to 99%). Further develop-
ment of a novel asymmetric organocatalytic system is ongoing in
our laboratory.
(6) Cai, X.; Wang, C.; Sun, J. Adv. Synth. Catal. 2012, 354, 359.
7) Aleman, J.; Fraile, A.; Marzo, L.; Ruano, J. L. G.; Izquierdo, C.;
Díaz-Tendero, S. Adv. Synth. Catal. 2012, 354, 1665.
(8) For selected reviews on asymmetric organocatalysis with cinchona
and their derivatives, see: (a) Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.;
McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. (b) Hoffmann, H.
M. R.; Frackenpohl, J. Eur. J. Org. Chem. 2004, 2004, 4293. (c) Chen, Y.-
C. Synlett 2008, 2008, 1919. (d) Marcelli, T.; Hiemstra, H. Synthesis
(
́
1
6
2
010, 2010, 1229.
(9) (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126,
9906. (b) Li, H.; Wang, Y.; Tang, L.; Deng, L. Angew. Chem., Int. Ed.
2005, 44, 105. (c) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128,
7
4
32. (d) Wu, F.; Li, H.; Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006,
5, 947. (e) Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem.,
Int. Ed. 2006, 45, 4301.
10) For selected examples of 6′-OH cinchona alkaloids as bifunctional
catalysts, see: (a) Wang, J.; Li, H.; Zu, L.; Wang, W. Org. Lett. 2006, 8,
391. (b) Wang, Y.; Li, H.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng,
(
1
L. J. Am. Chem. Soc. 2007, 129, 6364. (c) Bandini, M.; Sinisi, R.; Umani-
Ronchi, A. Chem. Commun. 2008, 4360. (d) Wang, H.-F.; Cui, H.-F.;
Chai, Z.; Li, P.; Zheng, C.-W.; Yang, Y.-Q.; Zhao, G. Chem. - Eur. J. 2009,
15, 13299. (e) Liu, Y.; Sun, B.; Wang, B.; Wakem, M.; Deng, L. J. Am.
Chem. Soc. 2009, 131, 418. (f) Chauhan, P.; Chimni, S. S. Eur. J. Org.
Chem. 2011, 2011, 1636. (g) Metro, T.-X.; Cochi, A.; Pardo, D. G.;
́
Cossy, J. J. Org. Chem. 2011, 76, 2594. (h) Chauhan, P.; Chimni, S. S.
RSC Adv. 2012, 2, 737.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01737.
(
11) For selected examples, see: (a) Li, H.; Song, J.; Liu, X.; Deng, L. J.
Descriptions of experimental procedures for compounds
and analytical characterization(PDF)
X-ray data for compound 4ag (CIF)
Am. Chem. Soc. 2005, 127, 8948. (b) Wang, J.; Li, H.; Zu, L.; Jiang, W.;
Wang, W. Adv. Synth. Catal. 2006, 348, 2047. (c) Dodda, R.; Goldman, J.
J.; Mandal, T.; Zhao, C. G.; Broker, G. A.; Tiekink, E. R. T. Adv. Synth.
Catal. 2008, 350, 537. (d) Lu, J.; Zhou, W.; Liu, F.; Loh, T. Adv. Synth.
Catal. 2008, 350, 1796. (e) Li, H.; Zhang, S.; Yu, C.; Song, X.; Wang, W.
Chem. Commun. 2009, 2136. (f) Xuan, Y.; Nie, S.; Dong, L.; Zhang, J.;
Yan, M. Org. Lett. 2009, 11, 1583. (g) Raimondi, W.; Lettieri, G.;
Dulcere, J. P.; Bonne, D.; Rodriguez, J. Chem. Commun. 2010, 46, 7247.
(h) Chauhan, P.; Chimni, S. S. Adv. Synth. Catal. 2011, 353, 3203.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: jlzhang@chem.ecnu.edu.cn.
Notes
(
(
(
i) He, P.; Liu, X.; Shi, J.; Lin, L.; Feng, X. Org. Lett. 2011, 13, 936.
j) Buyck, T.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2013, 52, 12714.
k) Zhao, Y.; Wang, X.-J.; Lin, Y.; Cai, C.-X.; Liu, J.-T. Tetrahedron 2014,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
70, 2523. (l) Cabanillas, A.; Davies, C. D.; Male, L.; Simpkins, N. S.
Chem. Sci. 2015, 6, 1350.
We are grateful for financial support from the National Natural
Science Foundation of China (21425205, 21372084), the
Shanghai Eastern Scholar Program, and the Shanghai Sailing
Program (16YF1402800).
(12) (a) Yu, X.; Du, B.; Wang, K.; Zhang, J. Org. Lett. 2010, 12, 1876.
(b) Xiao, Y.; Yu, Y.; Zhang, J. Angew. Chem., Int. Ed. 2008, 47, 1903.
(
(
c) Liu, F.; Yu, Y.; Zhang, J. Angew. Chem., Int. Ed. 2009, 48, 5505.
d) Liu, F.; Qian, D.; Li, L.; Zhao, X.; Zhang, J. Angew. Chem., Int. Ed.
2
010, 49, 6669. (e) Zhang, Z.-M.; Chen, P.; Li, W.; Niu, Y.; Zhao, X.;
REFERENCES
■
Zhang, J. Angew. Chem., Int. Ed. 2014, 53, 4350. (f) Zhou, L.; Zhang, M.;
Li, W.; Zhang, J. Angew. Chem., Int. Ed. 2014, 53, 6542. (g) Wang, Y.;
Zhang, P.; Qian, D.; Zhang, J. Angew. Chem., Int. Ed. 2015, 54, 14849.
(
1) For reviews of 2,3-dihydroisoxazoles, see: (a) Freeman, J. P. Chem.
Rev. 1983, 83, 241. (b) Gru
Chemistry of Heterocyclic Compounds; Taylor, E. C., Weissberger, A., Ed.;
John Wiley & Sons, 1991; Chapter 2, pp 416−647. (c) Pinho e Melo, T.
M. V. D. Eur. J. Org. Chem. 2010, 2010, 3363.
̈
nanger, P.; Vita-Finzi, P. Isoxazolines. In The
(
13) Catalyst 3i was reported as a ligand in an asymmetric
cycloaddition reaction; see: Wang, L.; Yang, D.; Han, F.; Li, D.; Zhao,
D.; Wang, R. Org. Lett. 2015, 17, 176.
(
2) (a) Atienza, J. M.; Susanto, D.; Huang, C.; McCarty, A. S.; Colicelli,
(
14) A similar catalyst was reported as an effective catalyst for
asymmetric aldol reaction; see: Zheng, Y.; Deng, L. Chem. Sci. 2015, 6,
510.
15) CCDC 1495440 (4ag) contains the supplementary crystallo-
graphic data for this compound.
16) (a) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc.
007, 129, 768. (b) Li, H.; Song, J.; Deng, L. Tetrahedron 2009, 65, 3139.
c) Deng, Y.; Zhang, Z.; Feng, Y.; Chan, A. S. C.; Lu, G. Tetrahedron:
Asymmetry 2012, 23, 1647.
J. J. Biol. Chem. 1999, 274, 4839. (b) Habeeb, A. G.; Praveen Rao, P. N.;
Knaus, E. E. J. Med. Chem. 2001, 44, 2921. (c) Cramer, R. D.; Jilek, R. J.;
Guessregen, S.; Clark, S. J.; Wendt, B.; Clark, R. D. J. Med. Chem. 2004,
6
(
4
7, 6777. (d) Hubich, A. I.; Zheldakova, T. A.; Chernikhova, T. V.;
Koroleva, E. V.; Lakhvich, F. A.; Sholukh, M. V. Biochem. Biophys. Res.
Commun. 2006, 341, 357. (e) Fraley, M. E.; Garbaccio, R. M.; Hartman,
G. D. PCT Int. Appl. WO2006/023440, 2006.
(
2
(
(
3) (a) Bruche,
Viani, F. Eur. J. Org. Chem. 1999, 1999, 1665. (b) Busque,
P.; Figueredo, M.; Font, J.; Gallagher, T.; Milan, S. Tetrahedron:
Asymmetry 2002, 13, 437. (c) Francois, D.; Maden, A.; Murray, W. V.
́
L.; Arnone, A.; Bravo, P.; Panzeri, W.; Pesenti, C.;
́
F.; de March,
́
̧
Org. Lett. 2004, 6, 1931. (d) Cantagrel, F.; Pinet, S.; Gimbert, Y.;
Chavant, P. Y. Eur. J. Org. Chem. 2005, 2005, 2694.
(
7
(
2
4) Ukaji, Y.; Inomata, K.; Wei, W.; Kobayashi, M. Heterocycles 2009,
8, 717.
5) Sakakura, A.; Hori, M.; Fushimi, M.; Ishihara, K. J. Am. Chem. Soc.
010, 132, 15550.
D
DOI: 10.1021/acs.orglett.6b01737
Org. Lett. XXXX, XXX, XXX−XXX