Metal- and Protection-Free [4 + 2] Cycloadditions of Alkynes with Azadienes: Assembly of Functionalized Quinolines

Article abstract of DOI:10.1021/acs.orglett.6b00817

A base promoted, protection-free, and regioselective synthesis of highly functionalized quinolines via [4 + 2] cycloaddition of azadienes (generated in situ from o-aminobenzyl alcohol) with internal alkynes has been discovered. The reaction tolerates a wide variety of functional groups which has been successfully extended with diynes, (2-aminopyridin-3-yl)methanol, and 1,4-bis(phenylethynyl)benzene to afford (Z)-phenyl-2-styrylquinolines, phenylnaphthyridine, and alkyne-substituted quinolines, respectively. The proposed mechanism and significant role of the solvent were well supported by isolating the azadiene intermediate and deuterium-labeling studies.

Full text of DOI:10.1021/acs.orglett.6b00817

Letter
pubs.acs.org/OrgLett
Metal- and Protection-Free [4 + 2] Cycloadditions of Alkynes with
Azadienes: Assembly of Functionalized Quinolines
Rakesh K. Saunthwal, Monika Patel, and Akhilesh K. Verma*
Department of Chemistry, University of Delhi, Delhi 110007, India
S
* Supporting Information
ABSTRACT: A base promoted, protection-free, and regioselective synthesis of highly functionalized quinolines via [4 + 2]
cycloaddition of azadienes (generated in situ from o-aminobenzyl alcohol) with internal alkynes has been discovered. The
reaction tolerates a wide variety of functional groups which has been successfully extended with diynes, (2-aminopyridin-3-
yl)methanol, and 1,4-bis(phenylethynyl)benzene to afford (Z)-phenyl-2-styrylquinolines, phenylnaphthyridine, and alkyne-
substituted quinolines, respectively. The proposed mechanism and significant role of the solvent were well supported by isolating
the azadiene intermediate and deuterium-labeling studies.
Scheme 1. Synthesis of Functionalized N-Heterocycles
wing to their diverse pharmaceutical and biological
1
Oactivities, quinoline nuclei are common templates for
steroids that are used as antimalarial, schistosomiasis, and
antifungal drugs.2 The construction of suitably functionalized
quinoline frameworks plays a vital role in many natural product
syntheses.3
A number of traditional approaches for synthesizing
quinolines have arisen from many renowned reactions, such
as the Skraup,4 Friedlaender,5 Combes,6 and Larock quinoline
syntheses7 and many others.8 The DeShong,9a Wang,9b and
Liang9c groups have demonstrated a facile route for the
synthesis of substituted quinolines. Recently, Ghorai,9d Red-
dy,9e and co-workers reported the synthesis of quinolines via
oxidative cycloisomerization and via hydroamination, respec-
tively. In 2014, Selig et al. explored the base-mediated, three-
step cascade synthesis of quinolines using protecting amino
aldehyde via Michael addition10 (Scheme 1a); however, a base-
promoted regioselective synthesis of quinolines by intermo-
lecular [4 + 2] cycloaddition has not been well explored.
The [4 + 2] cycloaddition reaction is among the most
powerful tool for generating carbocycles11 and N-hetero-
cycles,12 which is often difficult to form systems that are highly
congested or possess substituent arrays that are incompatible
with the reaction. An elegant work on [4 + 2] cycloaddition for
the synthesis of pyridines using a dienimine (azadiene)-type
motif was reported by Arndt et al.12d,e in 2008 (Scheme 1b).
Recently, the Rovis,13 Cheng,14a,b Chiba,14c and Bergman and
Ellman14d groups have demonstrated the N-protected azadiene
core moiety and alkynes for the synthesis of pyridines via
rhodium-catalyzed C−H functionalization (Scheme 1c). A
literature survey revealed that metal- and protection-free, base-
promoted intermolecular [4 + 2] cycloaddition for the
synthesis of quinoline remains elusive.
In continuation of our ongoing research on base-mediated
reactions15 and N-heterocyclic synthesis,16 we hypothesized
that the direct synthesis of quinoline could occur via KOH−
DMSO-promoted oxidation of benzyl alcohol to benzaldehyde
followed by the hydroamination though the reaction of 2-
aminobenzaldehyde with alkyne was unsuccessful (Scheme 1d,
route A, and Scheme 7 (i). We also speculated a modular route
Received: March 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00817
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
for the assembly of structurally diverse quinolines with excellent
regioselectivity via KOH−DMSO-mediated [4 + 2] cyclo-
addition of azadiene (can be generated in situ from o-
aminobenzyl alcohol) with internal alkyne (Scheme 1d, route
B).
With optimized reaction conditions in hand, we extended the
scope of the developed protocol with various symmetrical and
unsymmetrical aryl alkynes (Scheme 2). The reaction of
a,b
Scheme 2. Scope of Aryl Internal Alkynes
However, four major challenges have to be overcome:
(1) Intermolecular [4 + 2] cycloaddition of 2-aminobenzyl
alcohol must occur in the presence of base without using
any activation source/metal.
(2) Chemoselectivity: Aminobenzyl alcohol has two nucle-
ophilic sites, and the in situ generated azadienes also have
two nucleophilic sites. Thus, it is challenging to achieve
high chemoselectivity.
(3) Protection-free: It is tedious to perform the selective
quinoline synthesis without protection due to the
presence of two labile sites in the substrate.
(4) Regioselectivity: Besides the chemoselectivity, cyclo-
addition of the C−C triple bond should be regioselective.
Our investigation to explore the base-assisted [4 + 2]
cycloaddition began with the examination of a number of bases
reported in the literature using 2-aminobenzyl alcohol 1a and
diphenylacetylene 2a as a model substrates (Table 1). Inspired
a
b
c
Using optimized conditions (entry 5, Table 1). Isolated yield. 30 h.
substrate 1a with electron-neutral 2a, electron-releasing 2b, and
alkyne 2c afforded the product 3a−c in 75−78% yields. It is
worth noting that reaction of 1a with electron-rich thiophene-
substituted alkyne 2d provided the desired product 3d in 80%
yield. Reaction of substrate 1d with alkyne 2a provided the
tricyclic product 3e in 70% yield. Notably, the halogen-
substituted (2-aminophenyl)methanol 1b,c effectively gave the
corresponding quinolines 3f and 3g in 65 and 64% yields,
respectively. The unsymmetrical internal alkynes 2e−g afforded
the desired quinolines 3h−j regioselectively in 76−78% yields.
The reactions of unsymmetrical heteroalkynes 2h−k were well
implemented to form the intriguing fused products 3k−o in
66−82% yields. The electronic bias of the ring/substituents on
the C−C triple bond of the unsymmetrical alkynes plays an
important role in the regioselective formation of quinolines
3h−o (Scheme 2).17
a
Table 1. Reaction Development
b
entry
base
solvent
time (h) temp (°C) yield of 3a (%)
19d
KtOBu
KtOBu
KtOBu
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
24
24
24
24
24
24
24
24
12
12
25
50
80
80
90
100
90
90
90
90
trace
30
65
67
75
68
65
63
c
2
3
4
5
KOH
6
KOH
7
NaOH
CsOH
K2CO3
K3PO4
8
Encouraged by the above results, the reaction of 1a with aryl
alkyl unsymmetrical internal alkynes was performed (Scheme
3). The reaction of aryl alkyl substituted alkynes 4a−c provided
the desired quinolines 5a−c in 65, 64, and 66% yields,
respectively, with excellent regioselectivity. When a combina-
tion of unsymmetrical internal alkynes 4d−g containing a
9
10
c
a
Reactions were performed using 0.5 mmol of 1a, 2a (0.4 mmol), and
b
c
base (1.0 equiv) in 2.0 mL of solvent. Isolated yield. No reaction.
CCDC no. for 3a is 1435832.
a,b
Scheme 3. Scope of Aryl Alkyl Internal Alkynes
by Ghorai conditions,9d we carried out the reaction of 1a with
alkyne 2a using KtOBu in DMSO at 25 °C, but the desired
product 3a was obtained in only trace amounts (Table 1, entry
1). The promotional effect of temperature increases the yield of
the product 3a (Table 1, entries 2 and 3). On replacing KtOBu
with KOH, a slight improvement in the yield of the desired
product was observed (Table 1, entry 4). The reaction of 1a
with internal alkyne 2a at 90 °C fruitfully provided the
quinoline 3a in 75% yield (Table 1, entry 5). Further increasing
the reaction temperature declines the yield of product 3a
(Table 1, entry 6). A number of bases such as NaOH and
CsOH were examined, and it was found that the nature of
bases, as well as their counterions, influenced the reactivity of
cycloaddition reaction and provided the product 3a in
moderated yields (Table 1, entries 7 and 8), while no product
was observed with K2CO3 and K3PO4 (Table 1, entries 9 and
10) (for detailed optimization, see the SI).
a
b
c
Using optimized conditions (entry 5, Table 1). Isolated yield. 40 h.
Inseparable complex mixture. N.R. = no reaction.
d
B
DOI: 10.1021/acs.orglett.6b00817
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
substituted aryl ring on one side and a cyclohexyl ring on the
other side was used for the reaction, the functionalized
quinolines 5d−g were obtained in 66−74% yields. The reaction
of heteroalkyl alkynes 4h−m with substrate 1a afforded the
products 5j−m in 66−75% yields. The cycloaddition of (2-
amino-5-chlorophenyl)methanol 1b with alkyne 4c provided
the desired product 5n in 60% yield. Inferior results were
obtained in the reaction of 1a with oct-4-yne (4n) and diethyl
but-2-ynedioate (4o) (Scheme 3).
Scheme 7. Mechanistic Control Experiments
The scope of this base-assisted [4 + 2] cycloaddition was
further investigated by using phenyldiynes 6a−d (Scheme 4a).
Scheme 4. Scope of 1,3-Diyne and Pyridinyl Methanol
(confirmed by H, 13C and HRMS; along with unidentified
complex mixture) supports the formation of the desired
products via [4 + 2] cycloaddition (eq iii). The reaction of
azadiene intermediate 16 with alkyne 2a provided the quinoline
3a in 10% yield along with an unidentified complex mixture
which further supports the proposed mechanistic pathway (eq
iv). The deuterium-labeling experiment of 2-aminobenzylalco-
hol 1a with 2a in DMSO-d6 provided the desired product 3a′ in
70% yield with 90% exchange of D at the C-4 position (eq v).
In order to validate the exchange of deuterium with quinoline
protons, we heated the quinoline 3a with KOH−DMSO-d6 at
90 °C for 24 h, and only 20% of H−D exchange was observed
in product 3a″ (eq vi). The reaction of 1,2,3,4-tetrahydroquino-
line 17 in the presence of deuterated DMSO provided the
product 17′ with 56% incorporation of D at C-4 position (eq
vii), which supports the formation of transition state C in the
proposed mechanism (see Scheme 8).
1
Electron-donating diynes were tolerated in this transformation,
providing the (Z)-phenyl-2-styrylquinolines 7a−d in 59−63%
yields (see the SI for the mechanism). The regio- and
stereochemistry of the reaction was established on the basis
of chemical shifts, coupling constants (JH−H), and NOESY
studies. To our delight, the reaction of (2-aminopyridin-3-
yl)methanol 8 with alkyne 2a produced the biologically
important naphthyridine 9 albeit in lower yield (Scheme 4b).
Achieving the selectivity in base-mediated annulations of 2-
aminophenylmethanol 1 is a significant challenge with 1,4-
bisalkyne 10. When H and Cl groups were used as FG, the
reactions were well implemented to form the cyclized products
11a−b in 50−55% yields (Scheme 5).
Scheme 8. Proposed Mechanism
Scheme 5. Scope of Bis-alkyne
Reaction of secondary alcohol 12 with internal aryl alkynes
2a, 2e, and 2j was successful and provided the highly
functionalized quinolines 13a−d in good to moderate yields
(Scheme 6).
Based on the previous mechanistic studies, we put forward
the following mechanistic hypothesis as described in Scheme 8.
The mechanism is initiated by protonation15e,f of the 2-
aminobenzyl alcohol 1 via KOH−DMSO suspension, which
leads to the formation of imine type motif B. The anion of the
DMSO abstracts the proton and forms an intermediate 16.18
The reaction of azadiene intermediate 16 with alkyne would
form new N−C and C−C bonds (C) in a [4 + 2] cycloaddition
manner, which upon autoxidation12d successfully provided the
final quinoline product.
In conclusion, we have described an efficient base-promoted
metal- and protection-free synthesis of highly functionalized
quinolines from in situ generated azadiene and internal alkynes
via a [4 + 2] cycloaddition process with excellent chemo- and
regioselectivity. An electronic effect of the substrates plays a key
role in controlling the chemo- and regioselectivity in the
reaction. The three pairs for substrate scope, namely Ar−Ar,
Ar−alkyl, and diynes with 2-amino benzyl alcohols, were
Scheme 6. Scope of Secondary Alcohol
In order to support the proposed mechanistic pathway,
various preliminary experiments were performed (Scheme 7).
Initially, we thought the reaction was proceeding via aldehyde
formation; for validation of the possible reaction intermediate,
we performed the reaction of 2-aminobenzaldehyde 14 and 2-
aminoacetophenone 15 with 2a; however we failed to obtain
the desired products 3a and 13a (eqs i and ii). The results of
the above two control experiments rule out the formation of
product via hydroamination (Scheme 1, route A). We further
examined the reaction of 1a with KOH−DMSO at 90 °C; the
formation of the highly unstable azadiene intermediate 16
C
DOI: 10.1021/acs.orglett.6b00817
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Commun. 2015, 51, 13795. (i) Toh, K. K.; Sanjaya, S.; Sahnoun, S.;
Chong, S. Y.; Chiba, S. Org. Lett. 2012, 14, 2290. (j) Tanaka, S.;
Yasuda, M.; Baba, A. J. Org. Chem. 2006, 71, 800. (k) Bharate, J. B.;
Vishwakarma, R. A.; Bharate, S. B. RSC Adv. 2015, 5, 42020 and
references cited therein.
established for the synthesis of biologically active quinolines.
The preliminary control experiments succeeded in the isolation
of the azadiene intermediate, which supports the proposed
mechanistic pathway.
(9) (a) Sandelier, M.; DeShong, J. P. Org. Lett. 2007, 9, 3209.
(b) Zhang, Z.; Tan, J.; Wang, Z. Org. Lett. 2008, 10, 173. (c) Ali, S.;
Zhu, H.-T.; Xia, X.-F.; Ji, K.-G.; Yang, Y.-F.; Song, X.-R.; Liang, Y.-M.
Org. Lett. 2011, 13, 2598. (d) Rehan, M.; Hazra, G.; Ghorai, P. Org.
Lett. 2015, 17, 1668. (e) Kumar, Y. K.; Kumar, G. R.; Reddy, T. J.;
Sridhar, B.; Reddy, M. S. Org. Lett. 2015, 17, 2226.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00817.
■
S
(10) Selig, P.; Raven, W. Org. Lett. 2014, 16, 5192.
X-ray crystallographic data for 3a (CIF)
Experimental details, crystallographic information, and
spectral data for all new compounds (PDF)
(11) (a) Ginn, J. D.; Lynch, S. M.; Padwa, A. Tetrahedron Lett. 2000,
41, 9387. (b) Zhao, L.-M.; Zhang, A.-L.; Gao, H.-S.; Zhang, J.-H. J.
Org. Chem. 2015, 80, 10353. (c) Kim, S. M.; Park, J. H.; Chung, Y. K.
Chem. Commun. 2011, 47, 6719.
(12) (a) Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56, 5259.
(b) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Chem.
Rev. 2013, 113, 3084. (c) Groenendaal, B.; Ruijter, E.; Orru, R. V. A.
Chem. Commun. 2008, 5474. (d) Lu, J.-Y.; Arndt, H.-D. J. Org. Chem.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: averma@acbr.du.ac.in.
Notes
2007, 72, 4205. (e) Lu, J.-Y.; Keith, J. A.; Shen, W.-Z.; Schurmann, M.;
̈
Preut, H.; Jacob, T.; Arndt, H.-D. J. Am. Chem. Soc. 2008, 130, 13219.
(f) Wu, J.; Xu, W.; Yu, Z.-X.; Wang, J. J. Am. Chem. Soc. 2015, 137,
9489 references cited therein.
The authors declare no competing financial interest.
(13) (a) Neely, J. M.; Rovis, T. Org. Chem. Front. 2014, 1, 1010.
(b) Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47, 11846.
(c) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2014, 136, 2735.
(d) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 66.
(14) (a) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett.
2008, 10, 325. (b) Parthasarathy, K.; Cheng, C.-H. Synthesis 2009,
2009, 1400. (c) Too, P. C.; Noji, T.; Lim, Y. J.; Li, X.; Chiba, S. Synlett
2011, 2011, 2789. (d) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J.
Org. Chem. 2012, 77, 2501.
(15) (a) Joshi, M.; Patel, M.; Tiwari, R. K.; Verma, A. K. J. Org. Chem.
2012, 77, 5633. (b) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon,
V.; Larock, R. C. Angew. Chem., Int. Ed. 2009, 48, 1138. (c) Verma, A.
K.; Patel, M.; Joshi, M.; Likhar, P. R.; Tiwari, R. K.; Parang, K. J. Org.
Chem. 2014, 79, 172. (d) Patel, M.; Saunthawal, R. K.; Verma, A. K.
Tetrahedron Lett. 2014, 55, 1310. (e) Patel, M.; Saunthwal, R. K.;
Dhaked, D. K.; Bharatam, P. V.; Verma, A. K. Asian J. Org. Chem.
2015, 4, 894. (f) Patel, M.; Saunthwal, R. K.; Dhaked, D. K.; Bharatam,
P. V.; Verma, A. K. Asian J. Org. Chem. 2016, 5, 213.
(16) (a) Verma, A. K.; Danodia, A. K.; Saunthwal, R. K.; Patel, M.;
Choudhary, D. Org. Lett. 2015, 17, 3658. (b) Saunthwal, R. K.; Patel,
M.; Danodia, A. K.; Verma, A. K. Org. Biomol. Chem. 2015, 13, 1521.
(c) Saunthwal, R. K.; Patel, M.; Tiwari, R. K.; Parang, K.; Verma, A. K.
Green Chem. 2015, 17, 1434. (d) Saunthwal, R. K.; Patel, M.; Kumar,
S.; Verma, A. K. Tetrahedron Lett. 2015, 56, 677. (e) Saunthwal, R. K.;
Patel, M.; Kumar, S.; Danodia, A. K.; Verma, A. K. Chem. - Eur. J.
2015, 21, 18601.
(17) (a) Maity, B.; Gooßen, L. J.; Koley, D. Chem. Sci. 2015, 6, 2532.
(b) Rubin, M.; Trofimov, A.; Gevorgyan, V. J. Am. Chem. Soc. 2005,
127, 10243. (c) Verma, A. K.; Joshi, M.; Singh, V. P. Org. Lett. 2011,
13, 1630.
ACKNOWLEDGMENTS
■
This work was supported by SERB (SB/EMEQ-098/2014) and
(SB/S1/OC-84/2013). R.K.S and M.P. thank the UGC and
SERB for fellowships.
REFERENCES
■
(1) (a) Musiol, R.; Magdziarz, T.; Kurczyk, A. In Science against
Microbial Pathogens: Communicating Current Research and Technological
Advances; Mendez-Villas, A., Ed.; Formatex: Badajoz, 2011; Vol. 1, p
72. (b) Afzal, O.; Kumar, S.; Haider, M. R.; Ali, M. R.; Kumar, R.;
Jaggi, M.; Bawa, S. Eur. J. Med. Chem. 2015, 97, 871.
(2) (a) Achan, J.; Talisuna, A. O.; Erhart, A.; Yeka, A.; Tibenderana, J.
K.; Baliraine, F. N.; Rosenthal, P. J.; D’Alessandro, U. Malar. J. 2011,
10, 144. (b) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543. (c) Chen, Y.
J.; Fang, K. C.; Sheu, J.-Y.; Hsu, S. L.; Tzeng, C. C. J. Med. Chem. 2001,
44, 2374. (d) Kalluraya, B.; Sreenivasa, S. Farmaco 1998, 53, 399.
(3) (a) Balasubramanian, M.; Keay, J. G. Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 5, p 245. (b) Michael, J. P. Nat. Prod.
Rep. 1997, 14, 605.
(4) (a) Theoclitou, M. − E.; Robinson, L. A. Tetrahedron Lett. 2002,
43, 3907. (b) Yamashkin, S. A.; Oreshkina, E. A. Chem. Heterocycl.
Compd. 2006, 42, 701. (c) Saggadi, H.; Luart, D.; Thiebault, N.;
Polaert, I.; Estel, L.; Len, C. Catal. Commun. 2014, 44, 15.
(5) (a) Jia, C.-S.; Zhang, Z.; Tu, S.-J.; Wang, G.-W. Org. Biomol.
Chem. 2006, 4, 104. (b) Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.;
Lahoti, R. J.; Srinivasan, K. V. J. Org. Chem. 2003, 68, 9371. (c) Banon
́
-
̃
Caballero, A.; Guillena, G.; Naj
(6) (a) Sloop, J. C. J. Phys. Org. Chem. 2009, 22, 110. (b) Bergstrom,
F. W. Chem. Rev. 1944, 35, 77.
́
era, C. J. Org. Chem. 2013, 78, 5349.
(18) (a) Zhan, G.; Shi, M. − L.; He, Q.; Du, W.; Chen, Y.-C. Org.
Lett. 2015, 17, 4750. (b) Lai, Z.; Wang, Z.; Sun, J. Org. Lett. 2015, 17,
6058.
(7) (a) Stone, M. T. Org. Lett. 2011, 13, 2326. (b) Larock, R. C.;
Kuo, M.-Y. Tetrahedron Lett. 1991, 32, 569. (c) Zhang, X.; Yao, T.;
Campo, M. A.; Larock, R. C. Tetrahedron 2010, 66, 1177. (d) Larock,
R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291.
(8) (a) Zhao, P.; Yan, X.; Yin, H.; Xi, C. Org. Lett. 2014, 16, 1120.
(b) Liu, J.; Liu, F.; Zhu, Y.; Ma, X.; Jia, X. Org. Lett. 2015, 17, 1409.
(c) Midya, S. P.; Sahoo, M. K.; Landge, V.; Rajamohanan, P. R.;
Balaraman, E. Nat. Commun. 2015, 6, 8591. (d) Yan, R.; Liu, X.; Pan,
C.; Zhou, X.; Li, X.; Kang, X.; Huang, G. Org. Lett. 2013, 15, 4876.
(e) Jia, X.; Peng, F.; Qing, C.; Huo, C.; Wang, X. Org. Lett. 2012, 14,
4030. (f) Zhang, Y.; Wang, M.; Li, P.; Wang, L. Org. Lett. 2012, 14,
2206. (g) Sakai, N.; Tamura, K.; Shimamura, K.; Ikeda, R.;
Konakahara, T. Org. Lett. 2012, 14, 836. (h) Senadi, G. C.; Hu, W.-
P.; Garkhedkar, A. M.; Boominathan, S. S. K.; Wang, J. − J. Chem.
D
DOI: 10.1021/acs.orglett.6b00817
Org. Lett. XXXX, XXX, XXX−XXX