Exoselective 1,3-dipolar [3 + 6] cycloaddition of azomethine ylides with 2-acylcycloheptatrienes: Stereoselectivity and mechanistic insight

Article abstract of DOI:10.1021/acs.orglett.5b00011

A highly exo-selective 1,3-dipolar [3 + 6] cycloaddition of azomethine ylides with 2-acylcycloheptatrienes was realized with a Cu(I)/(S,R_p)-PPF-NHMe complex as the catalyst, leading to a diverse range of bridged piperidines with multiple functionalities in good yield with excellent stereoselectivity control. Theoretical calculations indicated a stepwise mechanism for this exo-selective [3 + 6] annulation, which accounts for the remarkable feature of this annulation: all of the larger substituent groups occupy the axial positions in the six-membered chairlike conformation of the piperidine ring.

Full text of DOI:10.1021/acs.orglett.5b00011

Letter
pubs.acs.org/OrgLett
Exoselective 1,3-Dipolar [3 + 6] Cycloaddition of Azomethine Ylides
with 2‑Acylcycloheptatrienes: Stereoselectivity and Mechanistic
Insight
Zhao-Lin He,†,⊥ Fu Kit Sheong,§,⊥ Qing-Hua Li,† Zhenyang Lin,*,§ and Chun-Jiang Wang*,†,‡
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 230012, China
§Department of Chemistry, The Hong Kong University of Science & Technology, Clear Water Bay, Kowloon, Hong Kong
S
* Supporting Information
ABSTRACT: A highly exo-selective 1,3-dipolar [3 + 6]
cycloaddition of azomethine ylides with 2-acylcyclohepta-
trienes was realized with a Cu(I)/(S,Rp)-PPF-NHMe complex
as the catalyst, leading to a diverse range of bridged piperidines
with multiple functionalities in good yield with excellent
stereoselectivity control. Theoretical calculations indicated a
stepwise mechanism for this exo-selective [3 + 6] annulation,
which accounts for the remarkable feature of this annulation:
all of the larger substituent groups occupy the axial positions in the six-membered chairlike conformation of the piperidine ring.
Scheme 1. Conformation Analysis for Endo- and Exo-Selective
Construction of Bridged Piperidines via 1,3-Dipolar [3 + 6]
Cycloaddition
itrogen-containing heterocycles are frequently found in
Nmany biologically active natural products and pharma-
ceuticals.1 Among the developed methodologies for heterocycle
synthesis, the 1,3-dipolar cycloaddition reaction is one of the
most powerful tools for the convergent construction of five-
membered heterocycles in organic synthesis2 due to the diverse
and readily available 1,3-dipoles (three-atom, 4π systems) and
dipolarophiles (two-atom, 2π systems). In view of the five-
membered heterocycles normally generated, a 1,3-dipolar
cycloaddition reaction was referred to as the [3 + 2]
cycloaddition reaction as well.3 Being coordinated with a chiral
ligand, the in situ formed metalated azomethine ylides have
received much attention in catalytic asymmetric 1,3-dipolar
cycloaddition reactions, providing an expedient approach to
enantioenriched pyrrolidine derivatives in the last decades.4,5
However, the 1,3-dipolar cycloaddition reaction has been seldom
utilized for synthesis of non-five-membered N-containing
heterocycles. Having utilized fulvenes6 and tropone7 as 6-π
dipolarophiles in the azomethine ylide involved 1,3-dipolar
cycloaddition reaction, we recently disclosed that with Cu(I)/
TF-BiphamPhos as the catalyst 2-acylcycloheptatrienes8 could
also serve as 6-π partners for constructing bridged piperidines
with multiple functionalities via exclusive endo selectivity control.
The six-membered heterocycles were each identified as having a
chairlike conformation in which the two substituents from ylides
occupy two equatorial positions and the cis-butadiene moieties
from cycloheptatrienes are in two axial positions (Scheme 1, left
side).
the [3 + 6]-annulation in an exclusively exo-selective manner
(Scheme 2). Formation of the exo-cycloadduct is challenging and
mechanistically intriguing considering that the two substituents
from ylides would have to be arranged in the seemingly energy-
disfavored axial positions, in view of the fact that the cis-butadiene
moiety from cycloheptatrienes has no choice but to occupy the
axial positions in the chairlike conformation because of ring
strain. In this paper, we present our results on the exo-selective
1,3-dipolar [3 + 6] cycloaddition of azomethine ylides with 2-
acylcycloheptatrienes in high yields and excellent enantioselec-
tivities catalyzed by the Cu(I)/(S,Rp)-PPF-NHMe complex. The
remarkable feature of this annulation, different from the case of
endo-selective 1,3-dipolar [3 + 6] cycloaddition, is that we
managed to generate piperidines in which the substituent groups
occupy the axial positions of the six-membered chairlike
conformation of the piperidine ring.
In view of the significance of access to any of the diastereomers
of chiral compounds with high diastereo-/enantioselectivity and
to further diversify synthetic methods for biologically important
piperidines,9 we decided to investigate the feasibility of realizing
Received: January 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00011
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Investigation of Exo-Selective 1,3-Dipolar [3 + 6]
Cycloaddition
Table 1. Substrate Scope for Catalytic Exo-Selective 1,3-
Dipolar [3 + 6] Cycloaddition of Azomethine Ylides 2 with 2-
a
Acylcycloheptatrienes 1
b
yield
c
entry
R
R′
3
(%)
ee (%)
1
2
3
4
5
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
p-ClC6H4 (2a)
o-ClC6H4 (2b)
m-ClC6H4 (2c)
p-CNC6H4 (2d)
Ph (2e)
3a
3b
3c
3d
3e
3f
88
78
82
73
74
56
65
72
81
72
63
65
79
85
77
75
92
75
72
98
99
99
>99
99
d
6
p-MeOC6H4 (2f)
p-MeC6H4 (2g)
m-MeC6H4 (2h)
2-naphthyl (2i)
2-furyl (2j)
99
e
7
3g
3h
3i
98
8
>99
>99
99
9
10
11
12
13
14
15
16
17
18
3j
PhCHCH (2k)
3k
3l
97
Et (2l)
94
p-ClC6H4 (1b)
m-ClC6H4 (1c)
p-ClC6H4 (2a)
p-ClC6H4 (2a)
3m
3n
3o
3p
3q
3r
3s
96
97
p-MeOC6H4 (1d) p-ClC6H4 (2a)
99
2-furyl (1e)
2-thienyl (1f)
Me (1g)
p-ClC6H4 (2a)
p-ClC6H4 (2a)
p-ClC6H4 (2a)
p-ClC6H4 (2a)
97
a
b
Yield of the isolated compound 3a. ee and dr were determined by
99
HPLC analysis using a chiral stationary phase.
98
e
19
H (1h)
98
a
All reactions were carried out with 0.45 mmol of 1 and 0.30 mmol of
b
2 in 2.0 mL of CH2Cl2. CuBF4 = Cu(MeCN)4BF4. Isolated yield.
Around 10% yield of the byproduct was separated, which was formed
via [3 + 2] cycloaddition14 (see the Supporting Information for
c
d
e
details). ee was determined by HPLC analysis. dr = 4:1. dr = 5:1.
Scheme 3. Postulated Catalytic Cycle
Figure 1. X-ray structure of (1R,6S,7R,9S)-exo-4.
Considering the crucial role of chiral ligands in asymmetric
catalysis,10 screening of some readily available and privileged
chiral ligands to investigate the potential variation of stereo-
selective control would be desirable and practicable. We started
our investigation by employing 2-benzoylcycloheptatriene 1a
and imine ester 2a as the model substrates. DTBM-Biphep (L2)
was first tested as the chiral ligand at room temperature with
CH2Cl2 as the solvent. Although excellent exo selectivity was
achieved with L2 in our previously reported Cu(I)-catalyzed 1,3-
dipolar [3 + 2] cycloaddition,11 only the same endo selectivity was
unexpectedly detected in this case. When (R,Sp)-L3 was next
screened in this transformation, partial inversion of diaster-
eoselectivity was observed, but the desired exo adduct was
formed as the minor isomer (22:78 dr) with only 48% ee.
Inspired by this promising result, we turned our attention to a
ferrocene-based ligand. The Cu(I)/(S,Rp)-tBu-Phosferrox (L4)
catalyst,12 giving high exo selectivity for 1,3 dipolar [3 + 2]
cycloaddition of azomethine ylide,13 was then evaluated in this
higher order cycloaddition. The cycloadduct was produced in
moderate yield favoring exoisomer in 73:27 dr, and the
enantioselectivity was remarkably enhanced to 97% ee.
Following the trend observed for the ferrocene-based chiral
P,N-ligand, (S,Rp)-PPF-NHMe (L5),7a which contains similar
B
DOI: 10.1021/acs.orglett.5b00011
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
heteroaromatic 2-furyl aldehyde, respectively, were also compat-
ible in this transformation, giving rise to the expected exo-3i and
-3j in good yield with 99% ee (entries 9 and 10). α,β-Unsaturated
cinammyl imino ester 2k also worked well in this process,
producing the desired exo-3k with 97% ee (entry 11).
Remarkably, less reactive aliphatic imino ester 3l was also proved
to be a viable substrate in this process, producing exo-3l in an
acceptable yield with excellent diastereoselectivity and 94% ee
(entry 12). The generality of dipolarophile partners was further
explored. In general, various 2-acyl cycloheptatrienes bearing
both aromatic and aliphatic groups were well tolerated in this
reaction (Table 1, entries 13−18). The consistently high
diastereoselectivity and excellent enantioselectivity observed
with 2-formylcycloheptatriene 1h is noteworthy (entry 19); as
such, a triene was shown to be a relatively challenging
dipolarophile affording only moderate enantioselectivity in our
previously reported endo-selective [3 + 6] cycloaddition
reaction.8
Figure 2. Free energy profile calculated for the 1,3-dipolar [3 + 6]
cycloaddition of imine ester 2a with 2-benzoylcycloheptatriene 1a on
the basis of the proposed mechanism shown in Scheme 3. The relative
free energies are given in kcal/mol.
With all the experimental results discussed above, we propose
a stepwise reaction mechanism (Scheme 3) that explains the
selectivities of the reaction. In the proposed mechanism, a two-
step process is involved during the cycloaddition reaction. We
expect that, as also suggested in previous work,15 the imine ester
will readily undergo deprotonation and coordinate to the metal
center, and the resulting metalated azomethine ylide acts as the
active catalyst (A) in the reaction. The reaction thus involves the
attack of the metalated azomethine ylide onto the Si-face of
dipolarophile unit. The electron-rich end of the azomethine ylide
dipole (B) first attacks the electron-deficient β-carbon on the
cycloheptatriene ring. Upon formation of the intermediate C, the
electron density shifts to the ω′ carbon through the 6-π system
on the 7-membered ring. At this point, the second attack takes
place from the ω′ carbon to the positive end of the azomethine
ylide dipole and closes the ring. Due to the chirality of the (S,Rp)-
PPF-NHMe ligand, the back side (with respect to the scheme) of
the azomethine ylide is blocked by the NHMe group, and it is this
steric hindrance that gives rise to the stereoselectivity of the
reaction. Subsequent protonation affords the bridged piperidine
adduct in boat conformation (D) with regeneration of the
catalyst. Due to the larger number of eclipsing interactions
existed in boat conformation (D), the six-membered heterocyclic
ring swiftly adopts the final chair conformation (E), in which all
the larger substituent groups occupy the seemingly energy-
disfavored axial positions.
chelating atoms as the Phosferrox ligand, was subsequently
employed in order to identify a more efficient catalyst in terms of
both exo selectivity and enantioselectivity control. To our
gratification, L5 not only displayed a great improvement on the
exo selectivity (dr >20:1) but also afforded a perfect
enantioselectivity of 98% ee. The absolute configuration of
cycloadduct 3a was determined as (1R,6S,7R,9S) by X-ray
analysis of the single crystal of its N-benzoylated derivative 4
(Figure 1), which validates the exo selectivity and confirms the
occupation of larger substituents in the axial positions of the six-
membered chairlike heterocyclic ring.
We next investigated the scope and generality of this exo-
selective catalytic system with regard to both azomethine ylide
precursors and 2-acylcycloheptatrienes. The representative
results of the investigation are summarized in Table 1. In
general, various imine esters 2 derived from aromatic aldehydes,
which bear electron-deficient (Table 1, entries 1−4), electron-
neutral (entries 5), or electron-rich substituents (entries 6−10),
afforded the desired exo adducts in good yields with good to high
diastereoselectivities and excellent enantioselectivities. The
substituent patterns on the aromatic ring have a marginal effect
on the diastereo-/enantioselectivity. Excellent stereoselectivity
was also observed for the sterically hindered o-chloro-substituted
imino ester 2b with the same reactivity being maintained (entry
2). Imine esters 2i and 2j derived from 2-naphthyl aldehyde and
Figure 3. Examination of the possibilities of different attacking modes leading to exo and endo cycloadducts. Energy reference point is taken to be the van
der Waals complex of the dipolarophile and metalated azomethine ylide on the pathway that gives rise to the experimentally observed exo cycloadduct.
C
DOI: 10.1021/acs.orglett.5b00011
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Sibi, M. P. Chem. Rev. 2008, 108, 2887. (d) Adrio, J.; Carretero, J. C.
Chem. Commun. 2011, 47, 6784. (e) Yu, J.; Shi, F.; Gong, L.-Z. Acc.
Chem. Res. 2011, 44, 1156.
From DFT calculations, we can find support for our
mechanistic arguments given above. We have chosen the
cycloaddition reaction that gives rise to 3a as our model system
in our DFT calculations. The DFT calculation results (Figure 2)
indicate that the proposed mechanism is energetically very
reasonable. We have also calculated the transition states for other
attacking modes leading to exo and endo cycloadduct as well as
different enantiomers (Figure 3, and see the Supporting
Information for more details). From these calculations, we
indeed found out that the barriers for other pathways are higher
than the one shown in Figure 2, thus explaining the high
selectivity observed experimentally. Meanwhile, the eclipsing
interactions in boat form force the heterocyclic ring to adopt the
chair conformation (Scheme 3, E was calculated to be 0.6 kcal/
mol lower in free energy than D).
In conclusion, we have successfully developed a rapid and
divergent approach to enantioenriched piperidine derivatives via
Cu(I)/(S,Rp)-PPF-NHMe-catalyzed exo-selective 1,3-dipolar [3
+ 6] cycloaddition of azomethine ylides with 2-acylcyclohepta-
trienes. The great importance of the bioactive piperidines bearing
multiple stereogenic centers makes the methodology particularly
interesting in organic synthesis. Theoretical calculations
indicated a stepwise mechanism for this exo-selective 1,3-dipolar
[3 + 6] cycloaddition, which accounts for all the larger
substituent groups occupying the axial positions in the six-
membered chairlike conformation of the piperidine ring.
(4) For selected recent examples on catalytic asymmetric 1,3-dipolar
cycloaddition, see: (a) Awata, A.; Ogawa, H.; Awata, A.; Sato, M.;
Watabe, M.; Yamanaka, M. Angew. Chem., Int. Ed. 2015, 54, 1595.
(b) Awata, A.; Arai, T. Angew. Chem., Int. Ed. 2014, 53, 10462. (c) Shi, F.;
Zhu, R.-Y.; Dai, W.; Wang, C.-S.; Tu, S.-J. Chem.Eur. J. 2014, 20, 2597.
(d) Eschenbrenner-Lux, M. S. V.; Kuchler, D.-B. P.; Ziegler, S.; Kumar,
̈
K.; Waldman, H. Angew. Chem., Int. Ed. 2014, 53, 2134. (e) Sun, W.;
Zhu, G.; Wu, C.; Li, G.; Hong, L.; Wang, R. Angew. Chem., Int. Ed. 2013,
52, 8633. (f) Huang, J.-Z.; Luo, S.-W.; Gong, L.-Z. Acta Chim. Sinica
2013, 71, 879. (g) Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuli, K.; Sato,
H. J. Am. Chem. Soc. 2010, 132, 5338. (h) Arai, T.; Yokoyama, N.;
Mishiro, A.; Sato, H. Angew. Chem., Int. Ed. 2010, 49, 7895. (i) He, L.;
Chen, X.-H.; Wang, D.-N.; Luo, S.-W.; Zhang, W.-Q.; Yu, J.; Ren, L.;
Gong, L.-Z. J. Am. Chem. Soc. 2011, 133, 13504. (j) Kim, H. Y.; Li, J.-Y.;
Kim, S.; Oh, K. J. Am. Chem. Soc. 2011, 133, 20750. (k) Wang, M.; Wang,
Z.; Shi, Y.-H.; Shi, X.-X.; Fossey, J. S.; Deng, W.-P. Angew. Chem., Int. Ed.
2011, 50, 4897. (l) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am. Chem.
Soc. 2008, 130, 5652. (m) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.;
Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321. (n) Zeng, W.; Chen,
G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem. Soc. 2007, 129, 750. For the
first examples on the catalytic asymmetric 1,3-dipolar cycloaddition
reactions of azomethine ylides, see: (o) Longmire, J. M.; Wang, B.;
Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. (p) Gothelf, A. S.;
Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem. 2002, 114,
4410; Angew. Chem., Int. Ed. 2002, 41, 4236.
(5) For the research works on 1,3-dipolar [3 + 2] cycloaddition from
this laboratory, see: (a) Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. J. Am.
Chem. Soc. 2008, 130, 17250. (b) Wang, C.-J.; Xue, Z.-Y.; Liang, G.; Lu,
Z. Chem. Commun. 2009, 2905. (c) Liu, T.-L.; Xue, Z.-Y.; Tao, H.-Y.;
Wang, C.-J. Org. Biomol. Chem. 2011, 9, 1980. (d) Liu, T.-L.; He, Z.-L.;
Wang, C.-J. Chem. Commun. 2011, 47, 9600. (e) Tong, M.-C.; Li, J.; Tao,
H.-Y.; Li, Y.-X.; Wang, C.-J. Chem.Eur. J. 2011, 17, 12922. (f) Liu, K.;
Teng, H.-L.; Yao, L.; Tao, H.-Y.; Wang, C.-J. Org. Lett. 2013, 15, 2250.
(g) Xue, Z.-Y.; Xiong, Y.; Wang, C.-J. Synlett 2014, 25, 2733. (h) Liu, T.;
Li, Q.; He, Z.; Zhang, J.; Wang, C. Chin. J. Catal. 2015, 36, 68.
(6) (a) Potowski, M.; Bauer, J. O.; Strohmann, C.; Antonchick, A. P.;
Waldmann, H. Angew. Chem., Int. Ed. 2012, 51, 9512. (b) He, Z.-L.;
Teng, H.-L.; Wang, C.-J. Angew. Chem., Int. Ed. 2013, 52, 2934.
(7) (a) Teng, H.-L.; Yao, L.; Wang, C.-J. J. Am. Chem. Soc. 2014, 136,
4075. (b) Liu, H.; Wu, Y.; Zhao, Y.; Li, Z.; Zhang, L.; Yang, W.; Jiang, H.;
Jing, C.; Yu, H.; Wang, B.; Xiao, Y.; Guo, H. J. Am. Chem. Soc. 2014, 136,
2625.
(8) Li, Q.-H.; Wei, L.; Wang, C.-J. J. Am. Chem. Soc. 2014, 136, 8685.
(9) (a) Kobayashi, J. I.; Hirasawa, Y.; Yoshida, N.; Morita, H. J. Org.
Chem. 2001, 66, 5901. (b) Mu, S.-Z.; Wang, J.-S.; Yang, X.-S.; He, H.-P.;
Li, C.-S.; Di, Y.-T.; Wang, Y.; Zhang, Y.; Fang, X.; Huang, L.-J.; Hao, X.-J.
J. Nat. Prod. 2008, 71, 564. (c) Zhang, C.-R.; Liu, H.-B.; Feng, T.; Zhu, J.-
Y.; Geng, M.-Y.; Yue, J.-M. J. Nat. Prod. 2009, 72, 1669. (d) Zhang, C.-
R.; Fan, C.-Q.; Dong, S.-H.; Liu, H.-B.; Zhou, W.-B.; Wu, Y.; Yue, J.-M.
Org. Lett. 2011, 13, 2440.
(10) Privileged Chiral Ligands and Catalysts; Zhou, Q.-L., Ed.; Wiley-
VCH: Weinheim, 2011.
(11) (a) Li, Q.-H.; Liu, T.-L.; Wei, L.; Zhou, X.; Tao, H.-Y.; Wang, C.-J.
Chem. Commun. 2013, 49, 9642. (b) Li, Q.; Huang, R.; Wang, C. Acta
Chim. Sinica 2014, 72, 830.
(12) (a) Tong, M.-C.; Chen, X.; Li, J.; Huang, R.; Tao, H.-Y.; Wang, C.-
J. Angew. Chem., Int. Ed. 2014, 53, 4608. (b) Tong, M.-C.; Chen, X.; Tao,
H.-Y.; Wang, C.-J. Angew. Chem., Int. Ed. 2013, 52, 12377.
(13) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.;
Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979.
(14) Erkizia, E.; Aldaba, E.; Vara, Y.; Arrieta, A.; Gornitzka, H.; Cossío,
F. P. ARKIVOC 2005, 189.
(15) Wang, M.; Wang, C.-J.; Lin, Z. Organometallics 2012, 31, 7870.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
* E-mail: chzlin@ust.hk.
* E-mail: cjwang@whu.edu.cn.
Author Contributions
⊥Z.-L.H. and F.K.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the 973 Program (2011CB808600),
NSFC (21172176, 21372180), and the Fundamental Research
Funds for the Central Universities. F.K.S. acknowledges support
from the Hong Kong Ph.D. Fellowship Scheme 2012/13 (PF11-
08816).
REFERENCES
■
(1) (a) Hou, X.-L.; Yang, Z.; Yeung, K.-S.; Wong, H. N. C. In Progress in
Heterocyclic Chemistry; Gribble, G. W., Joule, J., Eds.; Pergamon: Oxford,
2008; Vol. 19. (b) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39,
2791. (c) Fattorusso, E.; Scafati, O. T. Modern Alkaloids; Wiley-VCH:
Weinheim, 2008.
(2) (a) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984. (b) Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry towards Heterocycles and Natural Products; Padwa, A., Pearson,
W. H., Eds.; Wiley: New York, 2003.
(3) For recent reviews, see: (a) Naj
Chem., Int. Ed. 2005, 44, 6272. (b) Alvarez-Corral, M.; Munoz-Dorado,
M.; Rodríguez-García, I. Chem. Rev. 2008, 108, 3174. (c) Stanley, L. M.;
́
era, C.; Sansano, J. M. Angew.
́
̃
D
DOI: 10.1021/acs.orglett.5b00011
Org. Lett. XXXX, XXX, XXX−XXX