Synthesis of p-chloroazacalix[5]arene pentamethyl ether: Ring size-dependent deprotection of n-benzyl groups

Article abstract of DOI:10.3987/COM-12-S(N)48

Syntheses of chlorinated azacalix[4]arene and azacalix[5]arene have been investigated. While the preparation of the former failed in the final N-debenzylation step, the latter was successfully obtained. The observed ring size-dependent deprotection was in

Full text of DOI:10.3987/COM-12-S(N)48

HETEROCYCLES, Vol. 86, No. 1, 2012
159
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 159 - 164. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 22nd June, 2012, Accepted, 2nd August, 2012, Published online, 3rd August, 2012
DOI: 10.3987/COM-12-S(N)48
SYNTHESIS OF p-CHLOROAZACALIX[5]ARENE PENTAMETHYL
ETHER: RING SIZE-DEPENDENT DEPROTECTION OF N-BENZYL
GROUPS
Hirohito Tsue,* Kazuyuki Miyata, Daisuke Takahashi, Hiroki Takahashi,
Kohei Sasaki, and Rui Tamura
Graduate School of Human and Environmental Studies, Kyoto University,
Yoshida-nihonmatsu,
Sakyo-ku,
Kyoto
606-8501,
Japan.
e-mail:
tsue.hirohito.3c@kyoto-u.ac.jp
Abstract – Syntheses of chlorinated azacalix[4]arene and azacalix[5]arene have
been investigated. While the preparation of the former failed in the final
N-debenzylation step, the latter was successfully obtained. The observed ring
size-dependent deprotection was interpreted by steric effect.
Azacalixarenes have recently emerged as a new family of calixarene, and their intriguing host-guest
chemistry based on the introduction of nitrogen atoms as the bridging units are reported.1 Their
complexation phenomena particularly in the solid state are of great interest because the bridging nitrogen
atoms act as conjugation sites with the aromatic system to increase the electron density of the !-cloud,
thereby boosting intermolecular interactions with guest species. Indeed, we thus far reported that purely
organic crystals of azacalixarenes 1–42 rapidly and selectively captured CO2, a greenhouse gas of
environmental importance. Among them, azacalix[5]arene 2 exhibits the selective sorption of CO2 even at
ambient temperature and pressure conditions.2c,2d Besides, the smallest homologue 1 deposits single
crystals showing highly selective CO2 uptake, and its CO2 sorption state is successfully analyzed at an
atomic level by means of X-ray crystallography, demonstrating that CH/O interactions between the
tert-butyl groups of 1 and a molecule of CO2 trapped in the crystal lattice play an important role in the
observed highly selective CO2 uptake.2e
X
1: n = 4, X = t-Bu
2: n = 5, X = t-Bu
3: n = 6, X = t-Bu
4: n = 7, X = t-Bu
1': n = 4, X = Cl
2': n = 5, X = Cl
H
N
n
OMe
This paper is dedicated to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 1, 2012
In this context, we anticipate that the replacement of tert-butyl groups attached at para positions of 1 and
2 with halogen atoms leads to the enhancement of intermolecular interactions with CO2 because of the
formation of halogen bond.3 In conventional p-tert-butylcalixarenes with methylene bridges, halogenated
derivatives are easily available via a post halogenation method involving retro Friedel-Crafts
de-tert-butylation, followed by halogenation.4 In azacalix[4]arene 1, however, O-demethylation that is
essential before carrying out retro Friedel-Crafts reaction was found to be challenging because of the low
stability of the demethylated products to oxidation.5 In the present study, to establish synthetic pathway
for halogenated derivatives 1’ and 2’, we have selected chlorine as a halogen atom and employed a
convergent stepwise approach which is applied by us to the syntheses of tert-butyl derivatives 1 and 2.2d
As an outcome, a larger derivative 2’ was successfully obtained, whereas the synthesis of 1’ failed
because the final N-debenzylation step never proceeded in spite of our various attempts. Here we report
the ring size-dependent N-debenzylation reaction observed in the syntheses of 1’ and 2’.
We first investigated the preparation of 1’ by modifying our previously reported procedure for the
synthesis of tert-butyl derivative 1.2d As shown in Scheme 1, Buchwald-Hartwig aryl amination reaction
of monomers 5 and 6 was carried out to prepare liner trimer 7, which was subsequently reacted with
Boc-monoprotected monomer 8 to yield linear tetramer 9. The resulting product 9 was subjected to the
additional Boc protection of the terminal amino group, N-benzylation of the bridging nitrogen atoms, and
Cl
Cl
Br
Br
H2N
NHBoc
Cl
Cl
Cl
Cl
OMe
OMe
6 (2 equiv)
8
i
ii
H2N
NH2
Br
N
H
N
H
Br
OMe
OMe
OMe
OMe
5
7
R
Cl
Cl
N
Cl
Cl
Cl
Cl
vi
OMe
MeO
R
N
N
R
OMe
MeO
Br
N
N
N
NR2R3
R1
R1
R1
OMe
OMe
OMe
OMe
N
H
9: R1=R2=H, R3=Boc
10: R1=H, R2=R3=Boc
11: R1=Bn, R2=R3=H
Cl
Cl
iii
iv, v
12: R=Bn
1': R=H
Scheme 1. Attempted synthesis of p-chloroazacalix[4]arene 1’. (i) 5 mol% Pd(OAc)2, 7.5 mol% DPEphos,
2.4 equiv t-BuONa, PhMe, 80 °C, 16 h, 53%. (ii) 10 mol% Pd(OAc)2, 15 mol% DPEphos, 1.1 equiv
t-BuONa, PhMe, 90 °C, 15 h, 68%. (iii) 1.5 equiv Boc2O, 0.1 equiv DMAP, THF, reflux, 8 h, 75%. (iv)
3.1 equiv BnBr, 4.0 equiv NaH, DMF, 0 °C to rt, 14 h. (v) TFA, CH2Cl2, rt, 22 h, 59% in two steps. (vi)
20 mol% Pd(dba)2, 30 mol% (±)-BINAP, 2.0 equiv t-BuONa, PhMe, reflux, 18 h, 43%

HETEROCYCLES, Vol. 86, No. 1, 2012
161
deprotection of Boc groups to give linear tetramer 11. Tribenzylated azacalix[4]arene 126 was obtained in
43% yield by intramolecular cyclization of 11 using a Pd(0)-catalyzed Buchwald–Hartwig aryl amination
reaction. Despite our numerous efforts, however, the final deprotection of N-benzyl groups of 12 was not
accomplished, and this experimental result was in a sharp contrast to the same reaction for tert-butyl
derivative 13 of which the N-benzyl groups were smoothly cleaved in quantitative yield by using 20%
Pd(OH)2/C as a catalyst under a hydrogen atmosphere.2d All attempted hydrogenolysis reactions of
chlorinated derivative 12 under essentially the same conditions using PtO2, 10% Pd/C, or 20% Pd(OH)2/C
in the absence and presence of acetic acid as an additive resulted in the recovery of unreacted 12.7 This
was also the case for the homogeneous N-debenzylation reaction of 12 with TMSI, though successful
deprotection was achieved by this reagent in the synthesis of a larger homologue 2’ (vide infra).
Bn
t-Bu
t-Bu
Bn
N
OMe
OMe
MeO
MeO
Bn
N
N
N
H
t-Bu
t-Bu
13
To explore a reason for the observed unsuccessful N-debenzylation reaction of 12, DFT calculations at a
B3LYP/6-31G(d,p) level were carried out for chlorinated derivative 12 and tert-butyl derivative 13. As
shown in Figure 1, a large difference in electrostatic potentials was found for their bridging nitrogen
atoms. Negative areas at the nitrogen atoms of 12 are reduced as compared to those of 13, suggesting that
Figure 1. Electrostatic potential maps of (a) chlorinated derivative 12 and (b) tert-butyl derivative 13. All
hydrogen atoms are omitted for clarity.

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HETEROCYCLES, Vol. 86, No. 1, 2012
coordination to catalyst is less effective in 12 than 13. Besides, unlike conventional methylene-bridged
calix[4]arenes, molecular framework of azacalix[4]arenes is too rigid to permit ring inversion even in
solution.8 Accordingly, it seems likely that, because of electronic and steric effects, both heterogeneous
catalysts and TMSI uneasily approach the relevant reaction sites of 12 and thus lead to no debenzylation
reaction.
Contrary to the unsuccessful synthesis of 1’, we succeeded in preparing a larger homologue 2’ by
modifying our synthetic procedure established for tert-butyl derivative 2.2d As shown in Scheme 2, liner
pentamer 17 was obtained by Buchwald-Hartwig aryl amination reaction of monomers 5 and 6, followed
successively by N-benzylation of the bridging nitrogen atoms of 14, by Pd(0)-catalyzed aryl amination
reaction of 15 with benzophenone imine, and finally by hydrolysis of the resultant ketimine 16 with HCl.
Subsequent intramolecular ring-closing reaction of 17 was achieved by a Buchwald-Hartwig aryl
amination reaction to give tetrabenzylated azacalix[5]arene 18 in 65% yield. As a final step, all N-benzyl
groups of 18 were smoothly deprotected by TMSI to afford 2’9 in 76% yield. The successful synthesis of
2’ was unambiguously confirmed by X-ray crystallographic analysis10 (Figure 2), implying that the final
deprotection reactions of N-benzyl groups of 12 and 18 were dependent on their ring size. In other words,
it is very likely that azacalix[4]arene 12 blocks any reagents from approaching the reaction sites because
of steric hindrance arising from its rigid framework,8,11 and more flexible azacalix[5]arene 18 allows
enough space to promote N-debenzylation reaction to successfully produce 2’.
In conclusion, we have investigated the syntheses of 1’ and 2’ in which tert-butyl groups of 1 and 2 are
replaced by chlorine atoms. A larger derivative 2’ was successfully synthesized, whereas the preparation
of 1’ failed because the final N-debenzylation reaction never happened. It has been drawn from the
present study that, judging from the successful synthesis of 2’, steric hindrance rather than electronic
Cl
Cl
R
R
Br
Br
N
N
Cl
Cl
Cl
Cl
Cl
Cl
OMe
Cl
Cl
OMe
OMe
6 (1.5 equiv)
v
MeO
i
H2N
NH2
Br
N
N
N
N
R2
OMe
N
N
MeO OMe
R1
R1
R1
R1
R
R
OMe
OMe
OMe
OMe
OMe
14: R1=H, R2=Br
15: R1=Bn, R2=Br
16: R1=Bn, R2=NCPh2
17: R1=Bn, R2=NH2
5
N
H
ii
Cl
vi
Cl
iii
iv
18: R=Bn
2': R=H
Scheme 2. Synthesis of p-chloroazacalix[5]arene 2’. (i) 10 mol% Pd(OAc)2, 15 mol% DPEphos, 2.0
equiv t-BuONa, PhMe, 80 °C, 25 h, 21%. (ii) 6.2 equiv BnBr, 6.9 equiv NaH, DMF, 0 °C to rt, 7 h, 82%.
(iii) 1.0 equiv Ph2C=NH, 5 mol% Pd(dba)2, 15 mol% (±)-BINAP, 2.5 equiv t-BuONa, PhMe, 80 °C, 4 h,
43%. (iv) 1.2 M HCl, THF, rt, 5 h, 98%. (v) 10 mol% Pd(dba)2, 30 mol% (±)-BINAP, 2.5 equiv t-BuONa,
PhMe, 80 °C, 30 h, 65%. (vi) 4.0 equiv TMSI, CHCl3, 50 °C, 23 h, 76%

HETEROCYCLES, Vol. 86, No. 1, 2012
163
Figure 2. ORTEP drawing12 of p-chloroazacalix[5]arene 2’. The displacement ellipsoids are drawn at the
50% probability level. All hydrogen atoms but for the bridging NH atoms are omitted for clarity.
effect plays a major role in the observed ring size-dependent deprotection of N-benzyl groups.
Investigations on the gas sorption behaviors of 2’ are in progress in our laboratory to gain a further insight
into the host–guest chemistry of this new calixarene family in the solid state.
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research (C) (No. 23550052) from Japan
Society for the Promotion of Science (JSPS).
REFERENCES AND NOTES
1. H. Tsue, K. Ishibashi, and R. Tamura, in 'Heterocyclic Supramolecules I', ed. by K. Matsumoto,
Springer-Verlag, Berlin Heidelberg, 2008, pp. 73–96; (b) M.-X. Wang, Chem. Commun., 2008,
4541; (c) H. Tsue, K. Ishibashi, and R. Tamura, J. Synth. Org. Chem. Jpn., 2009, 67, 898; (d) M.-X.
Wang, Acc. Chem. Res., 2012, 45, 182.
2. (a) H. Tsue, K. Ishibashi, S. Tokita, H. Takahashi, K. Matsui, and R. Tamura, Chem. Eur. J., 2008,
14, 6125; (b) H. Tsue, K. Matsui, K. Ishibashi, H. Takahashi, S. Tokita, K. Ono, and R. Tamura, J.
Org. Chem., 2008, 73, 7748; (c) H. Tsue, K. Ishibashi, S. Tokita, and K. Sakai, Jpn. Unexam. Pat.
Appl. Publ., 2010-174002; (d) H. Tsue, K. Ono, S. Tokita, K. Ishibashi, K. Matsui, H. Takahashi, K.
Miyata, D. Takahashi, and R. Tamura, Org. Lett., 2011, 13, 490; (e) H. Tsue, H. Takahashi, K.
Ishibashi, R. Inoue, S. Shimizu, D. Takahashi, and R. Tamura, CrystEngComm, 2012, 14, 1021.
3. C. D. Gutsche, 'Calixarenes Revisited', ed. by J. F. Stoddart, Royal Society of Chemistry, Cambridge,
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5. K. Ishibashi, Thesis, Kyoto University, 2008.
6. 12: a light orange solid. mp 201–203 "; 1H NMR (CDCl3, 500 MHz) ! 7.28–7.18 (m, 15H, Ar-H),
6.74 (s, 4H, Ar-H), 6.58 (d, J = 2.5 Hz, 2H, Ar-H), 6.41 (d, J = 2.5 Hz, 2H, Ar-H), 5.11 (d, J = 16.5
Hz, 2H, ArCH2), 5.09 (d, J = 16.5 Hz, 1H, ArCH2), 4.88 (s, 1H, NH), 4.64 (d, J = 16.5 Hz, 2H,
ArCH2), 4.59 (d, J = 16.5 Hz, 1H, ArCH2), 3.07 (s, 6H, OMe), 2.95 (s, 6H, OMe); 13C NMR (CDCl3,
125 MHz) ! 147.7, 144.8, 143.3, 142.9, 141.9, 138.4, 137.9, 128.8, 128.7, 127.6, 127.5, 127.4, 127.2,
115.9, 115.8, 113.3, 113.1, 69.6, 60.2, 59.6, 59.2, 58.7, 53.4, 31.9, 29.8, 29.4; IR (KBr) " 3404 cm–1
("N-H); HRMS (ESI) Calcd for C49H42Cl4N4O4Na [M+Na]+: m/z 913.1852. Found: m/z 913.1851; Anal.
Calcd for C49H42Cl4N4O4: C, 65.93; H, 4.74; N, 6.28. Found: C, 65.71; H, 4.83; N, 6.28.
7. No cleavage of the C(sp2)-Cl bonds of 12 was observed after the heterogeneous hydrogenolysis
reactions. For reference, no dechlorination of 12 proceeded even by using a catalytic system of
[Cp*RhCl2]2 and 2-propanol (K. Fujita, M. Owaki, and R. Yamaguchi, Chem. Commun., 2002,
2964).
8. (a) H. Tsue, K. Ishibashi, S. Tokita, K. Matsui, H. Takahashi, and R. Tamura, Chem. Lett., 2007, 36,
1374; (b) K. Ishibashi, H. Tsue, H. Takahashi, and R. Tamura, Tetrahedron: Asymmetry, 2009, 20,
375.
9. 2’: a light orange solid. mp >300 "; 1H-NMR (CDCl3, 400 MHz) ! 6.90 (s, 10H, Ar-H), 6.27 (br s,
13
5H, NH), 3.27 (s, 15H, OMe); C-NMR (CDCl3, 100 MHz) ! 141.2, 138.7, 129.1, 114.0, 59.8;
HRMS (ESI) Calcd for C35H31Cl5N5O5 [M+H]+: m/z 776.0762. Found: m/z 776.0810; Anal. Calcd for
C35H30Cl5N5O5·0.75CH2Cl2: C, 51.02; H, 3.77; N, 8.32. Found: C, 51.30; H, 3.88; N, 8.13.
10. Crystal data for 2’: monoclinic, space group C2/c, a = 17.89(2) Å, b = 16.24(1) Å, c = 24.09(2) Å,
# = 92.41(1)°, V = 6991(10) Å3, Z = 8, Dc = 1.478 g cm–3, µ = 0.466 mm–1, T = 123(2) K, 7889
independent reflections, 475 refined parameters, R1 = 0.1199 (I > 2$(I)), R1 = 0.1759 (all reflections),
wR2 = 0.3006, S = 1.166. CCDC-886591 contains the supplementary crystallographic data for this
paper. Free copy of the data can be obtained via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; Fax:
+44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
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Commun., 2008, 2812; (b) K. Ishibashi, H. Tsue, H. Takahashi, S. Tokita, K. Matsui, and R. Tamura,
Heterocycles, 2008, 76, 541.
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