Regiospecific functionalization of azacalixaromatics through copper-mediated aryl C-H activation and C-O bond formation

Article abstract of DOI:10.1021/ol202874n

Regiospecific functionalization of tetraazacalix[1]arene[3]pyridines at the lower rim position of the benzene ring was achieved conveniently from their cross-coupling reaction with both aliphatic alcohols including chiral primary and secondary alcohols an

Full text of DOI:10.1021/ol202874n

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6560–6563
Regiospecific Functionalization of
Azacalixaromatics through Copper-
Mediated Aryl CÀH Activation and CÀO
Bond Formation
Zu-Li Wang, Liang Zhao, and Mei-Xiang Wang*
Key Laboratory for Organic Phosphorus Chemistry and Chemical Biology (Ministry of
Education), Department of Chemistry, Tsinghua University, Beijing 100084, China
wangmx@mail.tsinghua.edu.cn
Received October 27, 2011
ABSTRACT
Regiospecific functionalization of tetraazacalix[1]arene[3]pyridines at the lower rim position of the benzene ring was achieved conveniently from
their cross-coupling reaction with both aliphatic alcohols including chiral primary and secondary alcohols and phenol derivatives through the
Cu(ClO4)2-mediated aerobic aryl CÀH activation, which gave structurally well-defined arylÀCu(III) intermediates and a subsequent CÀO bond
formation reaction under very mild conditions.
Heteracalixaromatics,1 or heteroatom-bridged calixaro-
matics, are a new generation of macrocyclic host molecules
that have gained considerable attention in recent years in
the study of supramolecular chemistry. Being different from
the methylene linkage in the conventional calixarenes,2 het-
eroatoms such as nitrogen can adopt sp2 and sp3 electro-
nic configurations to form remarkably varied conjugation
systems with their adjacent aromatic rings, producing
macrocycles of unique conformational structures and of
fine-tunable sizes.3À7 Furthermore, introduction of het-
eroatoms into the bridging positions leads to the regulation
of binding ability of aromatic rings of resultant macrocyclic
(5) Gong, H.-Y.; Zhang, X.-H.; Wand, D.-X.; Ma, H.-W.; Zheng,
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r
10.1021/ol202874n
Published on Web 11/23/2011
2011 American Chemical Society

hosts.8À10 For example, tetraazacalix[4]pyridines exhibit
enhanced interactions with transition-metal ions8 and hydro-
gen-bond donors,7,9 whereas tetraoxacalix[2]arene[2]triazines
form complexes with halides via anionÀπ interactions.10
The fragment coupling approach1aÀd,3,4,11 and the one-
pot reaction protocol1aÀd,12 provide effective synthetic
routes to heteracalixaromatics. Starting from prefunction-
alized aromatic bisnucleophiles and biselectrophiles, a
few functionalized heteracalixaromatics have also been
synthesized.12a,d,13À15 An attractive strategy for the con-
struction of functionalized heteracalixaromatics, how-
ever, relies on the chemical fabrication of easily available
heteracalixaromatic compounds. In other words, basic
heteracalixaromatics can serve as platforms for the synth-
esis of sophisticated molecular architectures.1aÀd,3,12e,16
Advantageously, the “platform strategy” avoids the linear
or one-directional synthesis of each individual macro-
cycle. It is amenable to the construction of macrocyclic
heteracalixaromatic libraries. In addition, versatile chemi-
cal manipulations on both aromatic rings and bridging
positions lead to the flourishing of molecular diversity.
Moreover, the successful control of regio- and site-selec-
tivities provides an enabling method for the tailor-made
macrocyclic molecules.
efficiently with Cu(ClO4)2 under mild aerobic conditions
to yield stable and structurally well-defined arylÀCu(III)
complex 2a (Scheme 1). The arylÀCu(III) complex 2a
reacts readily at ambient temperature with a number of
nucleophiles including halides, cyanide, isothiocyanate,
and carboxylates to form CÀX, CÀC, CÀS, and CÀO
bonds, respectively, in almost quantitative yield. The chem-
istry of the well-defined aryl-Cu(III) species 3 has been
studied nicely by Ribas18 and Stalh19 (Figure 1). It is
their very recent report20 on the CÀO bond forma-
tion reaction that prompts us to disclose our study. In
this paper, we present the regiospecific functionalization
of azacalix[1]arene[3]pyridines by means of their cross-
coupling reaction with a variety of both aliphatic alcohols
including primary and secondary chiral alcohols and
phenol derivatives through arylÀCu(III) intermediates.
Figure 1. ArylÀCu(III) complex pioneered by Ribas18 and
Scheme 1. Cu(ClO4)2-Mediated Aryl CÀH Activation
Stalh.19
We began our investigation with the examination of the
reaction of arylÀCu(III) complex 2a with ethanol (2 equiv)
(Table 1). ArylÀCu(III) complex 2a was found stable and
inert toward ethanol as it was intact after refluxing in
acetonitrile for 12 h (entry 1, Table 1). A trace amount of
the desired CÀO bond-forming product 5a was observed
when 1 equiv of an organic base such as triethylamine
(entry 2, Table 1), 2,4,6-trimethylpyridine (collidine) (entry
3, Table 1), or 4-(N,N,-dimethylamino)pyridine (DMAP)
(entry 4, Table 1) was used. To our delight, 1,8-dia-
zabicyclo[5.4.0]undec-7-ene (DBU), a strong organic base,
We17 have discovered recently that azacalix[1]arene-
[3]pyridine 1a undergoes aryl CÀH bond activation
(9) Wang, Q.-Q.; Wang, D.-X.; Yang, H.-B.; Huang, Z.-T.; Wang,
M.-X. Chem.;Eur. J. 2010, 16, 7265.
(10) (a) Wang, D.-X.; Zheng, Q.-Y.; Wang, Q.-Q.; Wang, M.-X.
Angew. Chem., Int. Ed. 2008, 47, 7485. (b) Wang, D.-X.; Wang, Q.-Q.;
Han, Y.; Wang, Y.; Huang, Z.-T.; Wang, M.-X. Chem.;Eur. J. 2010,
16, 13053.
(16) (a) Yang, H.-B.; Wang, D.-X.; Wang, Q.-Q.; Wang, M.-X. J.
Org. Chem. 2007, 72, 3757. (b) Hou, B.-Y.; Wang, D.-X.; Yang, H.-B.;
Zheng, Q.-Y.; Wang, M.-X. J. Org. Chem. 2007, 72, 5218. (c) Hou, B.-
Y.; Zheng, Q.-Y.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem.
Commun. 2008, 3864. (d) Yao, B.; Wang, D.-X.; Gong, H.-Y.; Huang,
Z.-T.; Wang, M.-X. J. Org. Chem. 2009, 74, 5361. (e) Wang, L. X.;
Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2010, 75, 741.
(f) Chen, Y.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem. Commun.
2011, 47, 8112.
(17) Yao, B.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem.
Commun. 2009, 2899.
´
(18) Ribas, X.; Jackson, D. A.; Donnadieu, B.; Mahıa, J.; Parella, T.;
Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack, T. D. P.
Angew. Chem., Int. Ed. 2002, 41, 2991.
(11) Wang, L.-X.; Zhao, L.; Wang, D.-X.; Wang, M.-X. Chem.
Commun. 2011, 47, 9690.
(12) (a) Katz, J. L.; Feldman, M. B.; Conry, R. R. Org. Lett. 2005, 7,
3505. (b) Katz, J. L.; Selby, K. J.; Conry, R. R. Org. Lett. 2006, 8, 2755.
(c) Katz, J. L.; Geller, B. J.; Foster, P. D. Chem. Commun. 2007, 1026.
(d) Maes, W.; Van Rossom, W.; Van Hecke, K.; Van Meervelt, L.;
Dehaen, W. Org. Lett. 2006, 8, 4161. (e) Van Rossom, W.; Maes, W.;
Kishore, L.; Ovaere, M.; Van Meervelt; Dehaen, W. Org. Lett. 2008, 10,
585. (f) Zhang, C.; Chen, C.-F. J. Org. Chem. 2007, 72, 3880.
(13) (a) Hou, B.-Y.; Zheng, Q.-Y.; Wang, D.-X.; Wang, M.-X.
Tetrahedron 2007, 63, 10801. (b) Wu, J.-C.; Wang, D.-X.; Huang, Z.-
T.; Wang, M.-X. Tetrahedron Lett. 2009, 50, 7209.
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Ebenezer, W. J. Tetrahedron Lett. 2009, 50, 3923. (b) Clayden, J.;
Rowbottom, S. J. M.; Ebenezer, W. J.; Hutchings, M. G. Org. Biomol.
Chem. 2009, 7, 4871.
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71, 1233.
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9196. (b) Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.;
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ꢀ
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Org. Lett., Vol. 13, No. 24, 2011
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57%-68% (entries 1 to 4, Table 2), with the exception of
cyclopropylmethanol 4e, which gave 5e in 26% (entry 5,
Table 2). This is probably due to low stability of the small
ring substrate under the reaction conditions. The reaction
between 2a and isopropyl alcohol 4f, a secondary alcohol
species, proceeded analogously to afford 5f albeit in a
slightly low yield (entry 6, Table 2). However, no reaction
wasobservedfortertiarybutylalcohol4g(entry7,Table2).
The outcomes indicated clearly the steric effect in the CÀO
bond forming reaction between arylÀCu(III) complex 2a
and aliphatic alcohols 4.
Table 1. Reaction between ArylÀCu(III) Complex 2a and
Ethanol 4aa
Table 2. Synthesis of Alkoxylated Azacalixaromaticsa
entry
base (equiv)
T (°C)
time (h)
5ab (%)
1
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
40
12
12
12
12
12
12
24
12
12
12
12
12
12
12
12
12
0
2
Et3N (1)
trace
trace
trace
47
3
Collidine (1)
DMAP (1)
DBU (1)
4
5
6
DBU (2)
61
7
DBU (2)
62
8c
9d
10
11
12
13
14
15
16
DBU (2)
42
DBU (2)
59
DBU (2)
41
DBU (2)
rt
33
entry
4
ROH
EtOH
5b (%)
Na2CO3 (2)
K2CO3 (2)
NaOH (2)
KOH (2)
EtONa (2)
reflux
reflux
reflux
reflux
reflux
trace
trace
21
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
5a (61)
5b (57)
5c (56)
5d (68)
5e (26)
5f (46)
5g (0)
MeOH
42
BnOH
51
PhCtCCH2OH
c-C3H5CH2OH
iPrOH
tBuOH
a A mixture of 2a and ethanol (2 equiv) was reacted in acetonitrile.
b Isolated yield. c Ethanol (1 equiv) was used. d Ethanol (1 mL) was
used.
4g
a A mixture of 2a, alcohol 4 (2 equiv), and DBU (2 equiv) was
refluxed in acetonitrile for 12 h. b Isolated yield.
promotes the cross-coupling reaction to produce 5a in
47% isolated yield (entry 5, Table 1). The chemical yield
of 5a was improved to 61% when 2 equiv of DBU was
employed (entry 6, Table 1). Elongation of reaction time to
24h ledto62% yield (entry 7, Table1). Theuseofanexcess
amount of ethanol resulted in a comparable result (entry 9,
Table 1), whereas equimolar ethanol led to a low yield
(entry 8, Table 1). It should be noted that the identical re-
action performed at a lower temperature afforded dimin-
ished yields (entries 10 and 11, Table 1). Inorganic bases
showed no superiority over organic bases, as the employ-
ment of a weak inorganic base like Na2CO3 (entry 12,
Table 1) and K2CO3 (entry 13, Table 1) almost did not
effect the reaction, whereas NaOH (entry 14, Table 1) and
KOH (entry 15, Table 1) led to the formation of 5a only in
21% and 42%, respectively. The application of sodium
ethoxide yielded 5a in 51% (entry 16, Table 1).
Under the optimized conditions, a number of alkoxy-
lated tetraazacalix[1]arene[3]pyridines 5bÀf were synthe-
sized from aliphatic alcohols 4bÀf. As compiled in Table 2,
all primary alcohols examined such as ethanol 4a, metha-
nol 4b, benzylic alcohol 4c, and 3-phenylprop-2-yn-2-ol 4d
underwent equally efficient coupling reaction to produce
the corresponding CÀO bond-forming products 5aÀd in
In the presence of DBU, arylÀCu(III) complexes 2aÀc
were able to react smoothly in refluxing acetonitrile with
phenols 6aÀg tested in this study. For example, the cross-
coupling reaction between 2a and phenol 6a and its analog-
ues 6bÀf bearing either one electron-withdrawing halogen
and nitro group or electron-donating methyl group at the
ortho-, meta-, or para-position afforded diaryl ether-con-
taining tetraazacalixaromatics 7aÀf in yields ranging from
50% to 82% (entries 1À6, Table 3). Disubstituted phenol
derivative, 4-chloro-3-methylphenol 6g, underwent a simi-
lar reaction to yield 7g in 48% yield (entry 6, Table 3).
Azacalix[1]arene[3]pyridine that contains a p-methyl (2b)
or a p-chloro (2c) at the benzene ring is also functionalized
with 4-chlorophenol 6c effectively (entries 7 and 8, Table 3).
It is worth noting that substituents such as chloro, bromo,
and nitro are tolerated under reaction conditions, and they
provide a useful handle for furtherchemicalmanipulations.
The facile CÀO cross-coupling reaction encouraged
us to explore the construction of chiral macrocycles
using enantiomerically pure chiral alcohols as reactants.
Thus, following the same reaction procedure, chiral
tetraazacalix[1]arene[3]pyridine 8a was obtained in
6562
Org. Lett., Vol. 13, No. 24, 2011

Table 3. Synthesis of Aryloxylated Azacalixaromatics 7
Scheme 2. One-Pot Straightforward Synthesis of 5a
spectroscopic data, microanalyses, and X-ray crystallogra-
phy (see the Supporting Information). Figure 3 illustrates
the X-ray structure of 7c. In the crystalline state, the
molecule adopts a slightly distorted 1,3-alternate confor-
mation, with the benzene ring being almost face-to-face
paralleled to its distal pyridine ring. Interestingly, the
4-chlorophenyl moiety is included in the V-shaped cleft
formed by another two pyridine rings of the macrocycle.
The distances of the C(8) atom to the N(2) and N(6) atoms
are 3.06 and 3.28 A, respectively.
entry
2
6 ArOH
6a, PhOH
7a (%)
1
2
3
4
5
6
7
8
9
2a, R = H
2a, R = H
2a, R = H
2a, R = H
2a, R = H
2a, R = H
2a, R = H
2b, R = Me
2c, R = Cl
7a (64)
7b (65)
7c (79)
7d (50)
7e (73)
7f (82)
7g (48)
7h (78)
7i (66)
6b, 2-ClC6H4OH
6c, 4-ClC6H4OH
6d, 3-Me-C6H4OH
6e, 4-Br-C6H4OH
6f, 4-NO2-C6H4OH
6g, 4-Cl-3-Me-C6H3OH
6c, 4-Cl-C6H4OH
6c, 4-Cl-C6H4OH
a Isolated yield.
46%from (S)-2-methylbutanol, aprimaryalcoholwith aβ-
stereogenic center. The employment of (S)-2-phenyletha-
nol, a secondary chiral alcohol, in the reaction with 2a
afforded chiral macrocyclic product 8b in 35% (Figure 2).
Figure 3. X-ray structure of 7c.
In summary, we have established a straightforward
and convenient method for the regiospecific functiona-
lization of azacalix[1]arene[3]pyridines on the lower rim
position of the benzene ring by means of the Cu(ClO4)2-
mediated aryl CÀH bond activation and subsequent
CÀO bond formation with a variety of aliphatic alcohols
and phenols. The application of the resulting alkoxy-
lated and aryloxylated products in molecular recogni-
tion and self-assembly is being actively pursued in this
laboratory.
Figure 2. Chiral tetraazacalix[1]arene[3]pyridine derivatives 8.
The synthesis of regiospecifically functionalized azacalix-
[1]arene[3]pyridines does not necessarily require the isola-
tion of an arylÀCu(III) intermediate. To demonstrate the
efficacy of the copper-mediated CÀO cross-coupling reac-
tion in the synthesis of functionalized macrocyclic com-
pound, we conducted the preparation of 5a simply by
stirring at ambient temperature a mixture of 1a and
Acknowledgment. We thank the NNSFC (Grant Nos.
21132005, 21121004, and 20972161), MOST (Grant No.
2011CB932501), and Tsinghua University for financial
support.
Cu(OCl4)2 6H2O in chloroform and methanol (1:1) in
3
an open vial for 2 h followed by, after removal of solvent,
refluxing the residue with ethanol (2 equiv) and DBU
(2 equiv) in acetonitrile for 12 h (Scheme 2).
Supporting Information Available. Full experimental
details and characterization data; X-ray structure of 7c
(CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
The structure of the functionalized azacalix[1]arene-
[3]pyridine products was established on the basis of their
Org. Lett., Vol. 13, No. 24, 2011
6563