Enantioselective, Copper-Catalyzed Alkynylation of Ketimines to Deliver Isoquinolines with α-Diaryl Tetrasubstituted Stereocenters

Article abstract of DOI:10.1021/acs.orglett.6b02787

An enantioselective, copper-catalyzed alkynylation of cyclic α,α-diaryl ketiminium ions has been developed to deliver isoquinoline products with diaryl, tetrasubstituted stereocenters. The success of this reaction relied on identification of Ph-PyBox as the optimal ligand, i-Pr₂NEt as the base, and CHCl₃ as the solvent. A broad scope and functional group tolerance were observed. Notably, the use of both aryl and silyl acetylenes results in high yields and enantioselectivities. Mechanistic experiments are consistent with a dimeric or higher order catalyst.

Full text of DOI:10.1021/acs.orglett.6b02787

Letter
pubs.acs.org/OrgLett
Enantioselective, Copper-Catalyzed Alkynylation of Ketimines To
Deliver Isoquinolines with α‑Diaryl Tetrasubstituted Stereocenters
Srimoyee Dasgupta, Jixin Liu, Clarissa A. Shoffler, Glenn P. A. Yap, and Mary P. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: An enantioselective, copper-catalyzed alkynylation of
cyclic α,α-diaryl ketiminium ions has been developed to deliver
isoquinoline products with diaryl, tetrasubstituted stereocenters. The
success of this reaction relied on identification of Ph-PyBox as the
optimal ligand, i-Pr2NEt as the base, and CHCl3 as the solvent. A
broad scope and functional group tolerance were observed. Notably,
the use of both aryl and silyl acetylenes results in high yields and
enantioselectivities. Mechanistic experiments are consistent with a dimeric or higher order catalyst.
he prevalence of α-chiral cyclic amines in pharmaceuticals,
natural products, and otherbioactive moleculesmakesthem
Scheme 1. Enantioselective, Metal-Catalyzed Alkynylations of
Cyclic Iminium Ions
T
enticing targets for synthesis.1 In particular, cyclic α-tetrasub-
stituted amines are found in molecules possessing activity against
a range of diseases, including breast cancer, seizures, thrombosis,
and human immunodeficiency virus (HIV).2 However, methods
to prepare cyclic α-tetrasubstituted amines in high enantiopurity,
a requirement for their biomedical use, are limited.3 A powerful
approach tothese compounds would beenantioselective addition
to a ketimine or ketiminium ion. Most substrates for such
additions have been limited to those with electronically and/or
sterically different substituents on the electrophilic carbon.4
Enantioselective preparation of α-diaryl tetrasubstituted amines
remains a challenge; only two classes of carbon nucleophiles
(arenes, cyanide)havebeendeliveredinhighenantioselectivityto
cyclic diaryl ketimines.5−7 With an eye toward enantioselective
addition of a versatile carbon nucleophile to cyclic diaryl
ketimines, we envisioned enantioselective, copper-catalyzed
alkynylation may provide a useful solution. Although enantiose-
lective alkynylations of a variety of cyclic aldimines and
aldiminium ions to deliver α-trisubstituted amines are known
(Scheme 1, eq 1),5a,6,8 only a single report of enantioselective
alkynylation of a cyclic ketiminium ion exists. Maruoka has
impressively shown that a Cu(Ph-PyBox)/Brønsted acid catalyst
system enables alkynylation of alkyl-substituted isoquinolinium
ions (Scheme 1, eq 2).9,4 However, no methods exist for
enantioselective alkynylation of α,α-diaryl ketimines or iminium
ions with either cyclic or acyclic substrates. Given the similarity
between Maruoka’s conditions and our enantioselective, copper-
catalyzed alkynylation of cyclic diaryl oxocarbenium ions,10 we
envisioned that anenantioselective alkynylation of diaryliminium
ions may enable synthesis of the challenging α-diaryl tetrasub-
stituted amine motif (Scheme 1, eq 3). Herein we report the
successful development of this reaction, in which a tether enables
differentiation of the faces of a diaryl ketiminium ion to allow
synthesis of tetrahydroisoquinolines in excellent enantiomeric
enrichment. This reaction relies on a commercially available
copper precatalyst and chiral ligand, and boasts a broad scope in
the ketimine and alkyne. The alkyne provides a versatile
functional group for further manipulation.
We began by examining the alkynylation of 1-phenyl
dihydroisoquinoline 2a with phenyl acetylene. Dihydro-
isoquinoline 2a is easily prepared via a two-step procedure from
commercially available materials.11 Following precedent with
unsubstituted pyridines and isoquinolines,8h,l−n we acetylated in
situusingmethylchloroformate togenerateaketiminiumion. We
then added the mixture of ketiminium ion to the other reaction
components (alkyne, copper salt, ligand, base). In the presence of
an achiral copper(I) catalyst, alkynylation proceeded smoothly to
give up to an 81% yield (Table 1, entries 1−3). When CuI was
stirred with Ph-PyBox L1 for 30 min before addition of the other
Received: September 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
1, entries 18, 19). This result is particularly surprising with CuCl,
given that chloride is present due to the acylation with methyl
chloroformate.
Table 1. Optimization of Alkynylation
Under the optimized conditions (Table 1, entry 15), a broad
range of 1-arylisoquinolines undergo enantioselective alkynyla-
tion (Scheme 2). Alkynylation of 2a proceeded effectively, giving
entry
[Cu]
ligand temp (°C) yield (%) ee (%)
a
Scheme 2. Scope in Isoqinoline
1
CuI
−
rt
rt
rt
rt
4
81
65
50
85
65
89
75
39
61
76
72
60
80
77
81
(64)
95
95
91
−
2
Cu(MeCN)4PF6
CuSPh
CuI
−
−
3
−
−
4
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
L1
L1
L1
L1
37
53
20
10
11
0
5
CuI
6
CuI
4
7
CuI
4
8
CuI
4
9
CuI
4
10
11
12
13
14
15
16
17
18
19
CuI
4
0
b
c
CuI
4
19
0
CuI
4
d
d
CuI
4
89
92
91
95
91
35
33
CuI
−20
4
de
,
CuI
def
, ,
CuI
4
dg
,
CuI
4
dg
,
CuBr
CuCl
4
dg
,
4
a
Conditions: Ketimine 2a (0.1 mmol), [Cu] (10 mol %), ligand (12
mol %), phenylacetylene (1.2 equiv), ClCO2Me (1.0 equiv), iPr2NEt
(1.5 equiv), CH2Cl2 (0.15 M), 24 h, unless otherwise noted. Yields
determined by 1H NMR with 1,3,5-trimethoxybenzene as internal
standard. Ee’s determined by HPLC using a chiral stationary phase.
b
c
Et3N as base. MTBD (7-methyl-1,5,7-triazabiocyclo[4.4.0]dec-5-
d
e
f
ene) as base. CHCl3 as solvent. [2a] = 0.1 M. ClCO2Bn in place of
ClCO2Me. Isolated yield in parentheses. [2a] = 0.05 M. Iminium ion
g
a
Conditions: 2 (0.3 mmol), ClCO2Me (1.0 equiv), alkyne (1.2 equiv),
was not preformed; ClCO2Me added last.
CuI (10 mol %), L1 (12 mol %), iPr2NEt (1.5 equiv), CHCl3 (0.1 M),
4 °C, 48 h. Average isolated yields ( 5%) and ee’s ( 2%) of duplicate
b
c
experiments, unless noted otherwise. Set up outside glovebox. Single
d
e
experiment. [2] = 0.05 M. Iminium ion was not preformed;
ClCO2Me added last.
a 77% isolated yield and 91% ee. If this reaction is set up on the
benchtop, instead of the glovebox, a similar yield and ee are
observed. Both electron-donating and -withdrawing groups were
tolerated on the isoquinoline backbone (4−8), including an aryl
bromide, which offers a useful handle for elaboration (7). The
alkynylation also proceeded effectively for substrates with
substitution on the 1-phenyl group (9−13). In some cases,
reducing the concentration to 0.05 M led to increased
enantioselectivity. The aromatic isoquinoline can also be
employed to give product 14. As expected, the reversible
acylation of isoquinoline was less favorable than that for the
dihydroisoquinolines, initially leading to lower yields with our
original procedure. However, by following a one-pot procedure,
in which methyl chloroformate is added last, and by using a
reduced concentration ([2] = 0.05 M), a 69% yield and 90% ee
were obtained in a 1 g scale reaction. The crystal structure of 3
indicates that the copper acetylide adds to the re face.13
Interestingly, in the analogous alkynylation of 1-aryl isochroman
oxocarbenium ions, addition to the si face is dominant.10 We also
examined 1-methyl isoquinoline. However, no reaction was
observed, highlighting the benefit of Maruoka’s conditions for 1-
alkyl isoquinolines.9a
components, 85% yield and 37% ee were observed (Table 1, entry
4). By lowering the temperature to 4 °C, the ee was increased to
53%, albeit with a drop in yield (Table 1, entry 5). Other pyridine
(bis)oxazoline and oxazoline ligands L2−L6 provided no
improvement in enantioselectivity (entries 6−10). In addition,
theuse ofalternative bases, including MTBD, the optimal base for
the alkynylation of diaryl oxocarbenium ions, also resulted in
lower ee (Table 1, entries 11−12). However, by changing the
solvent to CHCl3, a dramatic increase in enantioselectivity was
observed (Table 1, entry 13).12 The enantioselectivity was
increased further by reducing the temperature to −20 °C, but at
thecostofyield(Table1, entry14). Decreasing theconcentration
was a more effective improvement, leading to an 81% yield and
91% ee (Table, 1 entry 15). Under these conditions, ClCO2Me
can be replaced by ClCO2Bn to give product in 64% isolated yield
and 95% ee (Table 1, entry 16). By decreasing the concentration
further ([2a] = 0.05 M), we achieved high yield and ee without
preforming the ketiminium ion in a separate reaction vessel
(Table 1, entry 17). Under these conditions, replacing CuI with
either CuBr or CuCl resulted in a dramatic decrease in ee (Table
B
DOI: 10.1021/acs.orglett.6b02787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A range of alkynes can also be used (Scheme 3). Both para and
meta substitution of aryl acetylenes are tolerated (15, 16).
Scheme 4. Elaboration of Products
a
Scheme 3. Scope in Alkyne
This reaction likely proceeds via a chiral copper acetylide,
which adds to the isoquinolinium ion. We are very interested in
understanding how the Cu/Ph-PyBox catalyst imparts enantio-
selectivity. As a first step, we need to understand the structure of
the catalyst. AlthoughPyBoxligands often enforceasquare planar
geometry onfour-coordinate metals, there is noelectronic benefit
to forcing four ligands into the same plane for Cu(I), making this
geometry unlikely. Bidentate coordination of the ligand is
possible, but the use of model ligands for bidentate coordination
(L7, L8) leads to racemic product 3 (L7: 67% yield by 1H NMR.
L8: 58% yield by 1H NMR). In addition, we observe a moderate
(+)-nonlinear effect under the optimized two-pot procedure.14,15
These results are similar to our observations in the alkynylation of
oxocarbenium ions catalyzed by a Cu/Ph-PyBox catalyst and
suggest that catalyst aggregation may occur.10
In addition, the reaction of CuI (1 equiv) and L1 (1 equiv) in
CH2Cl2 resulted in complex 30, [Cu2(L1)2I]3[Cu4I7], which has
1
been characterized by H and 13C NMR, as well as X-ray
a
Conditions: 2a (0.3 mmol), ClCO2Me (1.0 equiv), alkyne (1.2
crystallography.12 Notably, [Cu2(PyBox)2X2] complexes with
noncoordinating counteranions (PF6, OTf) have been ob-
served,16 but this is the first crystal structure with a bridging
halide counteranion.17 Complex 30 is catalytically competent,
delivering a high yield and 93% ee (Scheme 5B). Although these
equiv), CuI (10 mol %), L1 (12 mol %), iPr2NEt (1.5 equiv), CHCl3
(0.1 M), 4 °C, 48 h. Average isolated yields ( 6%) and ee’s ( 1%) of
b
duplicate experiments, unless noted otherwise. Single experiment.
c
d
[2a] = 0.05 M. Iminium ion was not preformed; ClCO2Me added
last.
However, o-methyl phenylacetylene resulted in a nearly racemic
product, albeit with an excellent yield (17). Alkynes with aryl
chloride 18, ether 19, ester 20, and nitrile 21 groups participated
effectively. For alkyl acetylenes, high yields, but low enantiose-
lectivities, were observed, with lower ee’s when a branched alkyl
group is used (22, 23). We also examined silyl acetylenes. We
observed only a 9% ee in the addition of trimethylsilyl acetylene
24. However, by increasing the phenyl groups on silicon, steadily
higher ee’s were seen. Triphenylsilyl acetylene 26 was formed in
good yield and 98% ee. A rationale for the low ee’s observed with
alkyl and trimethylsilyl acetylenes currently eludes us. One
possibility is that these alkynes or their decomposition products
(e.g., allenes for alkyl acetylenes) react with the copper catalyst to
generate a less enantioselective catalyst. However, addition of
trimethylsilylacetylene, 1-octyne, or 1,2-octadiene to the model
reaction (addition of phenyl acetylene to 2a) resulted in only
minor decreases in yield and ee.11 This vague outcome suggests
further studies are necessary to understand the low enantiose-
lectivity observed with these substrates.
Scheme 5. Structure and Reactivity of Complex 30
To demonstrate the utility of the alkyne, we performed several
elaborations (Scheme 4). Alkyne 3 was reduced to (S)-27 in
quantitative yield with only a slight decrease inee. Hydrogenation
of14alsoledto(S)-27,showingthattherefaceoftheiminiumion
is attacked for both dihyroisoquinolines and aromatic isoquino-
lines.11 The alkyne can also be oxidized to diketone 28 in good
yield and 100% conservation of ee. Deprotection of triphenylsi-
lane26proceededinanunoptimized45%yield, againwithnoloss
in enantiomeric enrichment.
results do not exclude the possibility that a higher-order complex
is simply an off-cycle reservoir for an active monomeric catalyst,
we currently favor a dicopper acetylide as the catalytic
intermediate. This mechanism is consistent with the well-
recognized importance of such dicopper acetylides in copper
acetylide chemistry.16,18 Ongoing mechanistic studies are
directed toward developing a stereochemical model based on
C
DOI: 10.1021/acs.orglett.6b02787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2001, 123,10784. (c)Nishimura, T.;Noishiki, A.;ChitTsui, G.;Hayashi,
T. J.Am.Chem. Soc.2012,134,5056.(d)Nishimura,T.;Noishiki, A.;Ebe,
Y.; Hayashi, T. Angew. Chem., Int. Ed. 2013, 52, 1777.
(6) For a single example ofalkynlation of a1-phenylisoquinoline in75%
yield (0% ee), see: Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143.
(7) For enantioselective reduction of diaryl ketimines, see: Nguyen, T.
such an intermediate, as well as understanding the effects of
concentration and base on the enantioselectivity.
In summary, we developed a copper-catalyzed alkynylation of
1-aryl isoquinolinium ions that delivers cyclic α-diaryl tetrasub-
stituted amines in good yields and high enantioselectivities. This
reaction employs a catalyst with commercially available
components, and a wide range of isoquinolines and alkynes can
be used. Notably, the addition of triphenylsilylacetylene is
effective, providing the potential for elaboration of the silyl-
protected alkyne. Our mechanistic studies are consistent with an
aggregated Cu/L1 complex as the active catalyst, consistent with
therecognizedimportanceofdicopperspeciesincopperacetylide
chemistry. Efforts are ongoing to expand the scope and more
deeply understand the mechanism.
B.; Bousserouel, H.; Wang, Q.; Guer
257.
́
itte, F. Adv. Synth. Catal. 2011, 353,
(8) (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem.
2004, 2004, 4095. (b) Kumagai, N.; Shibasaki, M. Bull. Chem. Soc. Jpn.
2015, 88, 503. (c) Ohshima, T. In Comprehensive Chirality; Carreira, E.
M., Yamamoto, H., Eds.; Elsevier: Amsterdam, 2012; p 355. (d) Trost, B.
M.;Bartlett, M. J. ModernAlkyneChemistry;Wiley-VCHVerlagGmbH&
Co. KGaA: 2014; p 201. (e) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (f) Li,
Z.; MacLeod, P. D.; Li, C.-J. Tetrahedron: Asymmetry 2006, 17, 590.
(g) Lin, W.; Cao, T.; Fan, W.; Han, Y.; Kuang, J.; Luo, H.; Miao, B.; Tang,
X.; Yu, Q.; Yuan, W.; Zhang, J.; Zhu, C.; Ma, S. Angew. Chem., Int. Ed.
2014, 53, 277. (h) Pappoppula, M.; Cardoso, F. S. P.; Garrett, B. O.;
Aponick, A. Angew. Chem., Int. Ed. 2015, 54, 15202. (i) Perepichka, I.;
Kundu, S.; Hearne, Z.; Li, C.-J. Org. Biomol. Chem. 2015, 13, 447. (j) Sun,
S.; Li, C.; Floreancig, P. E.; Lou, H.; Liu, L. Org. Lett. 2015, 17, 1684.
(k) Yu, J.; Li, Z.; Jia, K.; Jiang, Z.; Liu, M.; Su, W. Tetrahedron Lett. 2013,
54, 2006. (l) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007, 129,
9300. (m)Black, D. A.;Arndtsen, B. A. Org. Lett. 2004, 6, 1107. (n)Black,
D. A.; Beveridge, R. E.; Arndtsen, B. A. J. Org. Chem. 2008, 73, 1906.
(9) (a) Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem., Int. Ed.
2011, 50, 8952. (b) For enantioselective alkynylation of a
trifluoromethyl-substituted cylic ketimine using a stoichiometric chiral
ligand, see: Jiang, B.; Si, Y.-G. Angew. Chem., Int. Ed. 2004, 43, 216.
(10) Dasgupta, S.; Rivas, T.; Watson, M. P. Angew. Chem., Int. Ed. 2015,
54, 14154.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b02787.
Experimental details and data (PDF)
Crystal structures (CIF, CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mpwatson@udel.edu.
ORCID
(11) See the Supporting Information.
Mary P. Watson: 0000-0002-1879-5257
Notes
(12) We do not yet understand this dramatic solvent effect. See the
Supporting Information for discussions and further experiments.
(13) CCDC 1499232 (14) and CCDC 1499233 (30) contain the
supplementary crystallographic data for this paper. These can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Acknowledgement is gratefully made to the National Science
Foundation (CAREER CHE 1151364). C.A.S. thanks NSF REU
1263018. DatawereacquiredatUDoninstrumentsobtainedwith
assistance of NSF and NIH funding (NSF CHE0421224,
CHE1229234, CHE0840401, and CHE1048367; NIH P20
GM104316, P20 GM103541, and S10 OD016267).
(14) In contrast, no nonlinear effect was observed under the one-pot
procedure. See the Supporting Information.
(15) Girard, C.; Kagan, H. Angew. Chem., Int. Ed. 1998, 37, 2922.
(16) (a) Díez, J.; Gamasa, M. P.; Panera, M. a. Inorg. Chem. 2006, 45,
10043. (b) Panera, M. a.; Díez, J.; Merino, I.; Rubio, E.; Gamasa, M. P.
Inorg. Chem. 2009, 48, 11147. (c) Nakajima, K.; Shibata, M.;
Nishibayashi, Y. J. Am. Chem. Soc. 2015, 137, 2472.
(17)Forexamplesofmetal/PyBoxcomplexeswithbridginganions,see:
(a) Cuervo, D.; Díez, J.; Gamasa, M. P.;Gimeno, J. Organometallics 2005,
24, 2224. (b) Paredes, P.; Díez, J.; Gamasa, M. P. Organometallics 2008,
27, 2597. (c) Paredes, P.; Díez, J.; Gamasa, M. P. J. Organomet. Chem.
2008, 693, 3681. (d) Zhu, Y.-Y.; Cui, C.; Li, N.; Wang, B.-W.; Wang, Z.-
M.; Gao, S. Eur. J. Inorg. Chem. 2013, 2013, 3101. (e) Staples, R. J.;Aye, Y.
J. Chem. Crystallogr. 2008, 38, 49.
(18) (a) Ahlquist, M.; Fokin, V. V. Organometallics 2007, 26, 4389.
(b) Díez, J.; Gamasa, M. P.; Gimeno, J.; Aguirre, A.; García-Granda, S.;
Holubova, J.; Falvello, L. R. Organometallics 1999, 18, 662. (c) Mealli, C.;
Godinho, S. S. M. C.; Calhorda, M. J. Organometallics 2001, 20, 1734.
(d) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem., Int. Ed.
2005, 44, 2210.
REFERENCES
■
(1) (a) Bentley, K. W. Nat. Prod. Rep. 2004, 21, 395. (b) Chrzanowska,
M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341. (c) Welsch, M. E.;
Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347.
(2) (a) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus,
N. A.; Bacheler, L. T.; Diamond, S.; Jeffrey, S.; Klabe, R. M.; Cordova, B.
C.; Garber, S.; Logue, K.; Trainor, G. L.; Anderson, P. S.; Erickson-
Viitanen, S. K. J. Med. Chem. 2000, 43, 2019. (b) Renaud, J.; Bischoff, S.
F.; Buhl, T.; Floersheim, P.; Fournier, B.; Halleux, C.; Kallen, J.; Keller,
H.; Schlaeppi, J.-M.; Stark, W. J. Med. Chem. 2003, 46, 2945. (c) Stilz, H.
U.; Jablonka, B.; Just, M.; Knolle, J.; Paulus, E. F.; Zoller, G. J. Med. Chem.
1996, 39, 2118. (d) Wong, E. H.; Kemp, J. A.; Priestley, T.; Knight, A. R.;
Woodruff, G. N.; Iversen, L. L. Proc. Natl. Acad. Sci. U. S. A. 1986, 83,
7104. (e) Anderson, P.; Christy, M. A.; Evans, B. E. US4399141, 1983.
(3) Riant, O.; Hannedouche, J. Org. Biomol. Chem. 2007, 5, 873.
(4) For enantioselective alkynylations of acyclic ketimines with
trifluoromethyl, ester, and/or alkyl substituents, see: (a) Huang, G.;
Yang, J.;Zhang, X. Chem. Commun. 2011, 47, 5587. (b)Zhang, F.-A.; Ma,
H.; Zheng, Y.; Ma, J.-A. Tetrahedron 2012, 68, 7663. (c) Huang, G.; Yin,
Z.; Zhang, X. Chem. - Eur. J. 2013, 19, 11992. (d) Yin, L.; Otsuka, Y.;
Takada, H.; Mouri, S.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Org. Lett.
2013, 15, 698.
(5) (a) Ahamed, M.; Todd, M. H. Eur. J. Org. Chem. 2010, 2010, 5935.
(b) Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
D
DOI: 10.1021/acs.orglett.6b02787
Org. Lett. XXXX, XXX, XXX−XXX