Synthesis of diazacalix[8]arene and triazacalix[12]arene methyl ethers via intramolecular aryl amination

Article abstract of DOI:10.1021/ol8028912

Azacalixarenes derived from p-tert-butylphenol are generated by an intramolecular aryl amination strategy as the ring-closing step. The reaction produces the first examples of larger p-tert-butylcalixarenes with regioselective substitution of bridging met

Full text of DOI:10.1021/ol8028912

ORGANIC
LETTERS
2009
Vol. 11, No. 4
895-898
Synthesis of Diazacalix[8]arene and
Triazacalix[12]arene Methyl Ethers via
Intramolecular Aryl Amination
Kenneth V. Lawson, Ashlee C. Barton, and John D. Spence*
Department of Chemistry, California State UniVersity, Sacramento, 6000 J Street,
Sacramento, California 95819
jspence@csus.edu
Received December 15, 2008
ABSTRACT
Azacalixarenes derived from p-tert-butylphenol are generated by an intramolecular aryl amination strategy as the ring-closing step. The reaction
produces the first examples of larger p-tert-butylcalixarenes with regioselective substitution of bridging methylenes with nitrogen atoms.
Macrocyclic oligomers of p-alkylphenols and formaldehyde,
the original members of the calix[n]arene family,1 have
received widespread interest as molecular hosts. The one-
pot syntheses of p-tert-butylcalix[4], [6], and [8]arenes have
made these major calixarenes the most thoroughly studied
analogs. The small cavity size of p-tert-butylcalix[4]arene
imparts the greatest amount of conformational rigidity,
leading to the well-defined cone, partial cone, 1,2-alternate,
and 1,3-alternate conformations. p-tert-Butylcalix[8]arene,
on the other hand, is much more fluid in solution as a result
of a larger annulus and is believed to exist in either a pleated
loop2 or pinched double cone conformation.3 Furthermore,
rich functionalization strategies are available for p-tert-
butylcalix[n]arenes along their upper rim p-alkyl and lower
rim phenolic groups to fine-tune their conformational and
binding properties.
Recently focus has shifted to explore functionalization of
the bridging methylene groups to develop heteroatom-bridged
derivatives of calix[n]arenes.4 Replacement of the bridging
methylene groups with heteroatoms can alter the conforma-
tional properties of the macrocycle through changes in bond
lengths and angles associated with the heteroatom in addition
to participation of the heteroatom in hydrogen bonding along
the lower rim. Furthermore, the heteroatom provides ad-
ditional binding sites to the macrocycle and, in the case of
nitrogen and sulfur, new avenues to further functionalize the
bridge position. Heteroatom-bridged derivatives of the parent
p-tert-butylcalix[4]arene 1 (Figure 1) include mono-, di-, tri-,
and tetrathiacalix[4]arene 2,5 tetrasilacalix[4]arene 3,6 and
tetraazacalixarene 4,7 as well as the expanded homooxa- and
(1) For reviews on calixarenes, see: (a) Gutsche, C. D. Calixarenes An
Introduction, 2nd ed.; Stoddart, J. R., Ed.; Royal Society of Chemistry:
Cambridge, UK, 2008. (b) Calixarenes 2001; Asfari, Z., Bo¨hmer, V.,
Harrowfield, J., Vicens, J., Eds.; Kluwer Academic Publishers: Dordrecht,
The Netherlands, 2001.
(4) For reviews, see: (a) Ko¨nig, B.; Fonseca, M. H. Eur. J. Inorg. Chem.
2000, 2303–2310. (b) Wang, M.-X. Chem. Commun. 2008, 4541–4551.
(c) Maes, W.; Dehaen, W. Chem. Soc. ReV. 2008, 37, 2393–2402. (d) Tsue,
H. Top. Heterocycl. Chem. 2008, 17, 73–96.
(2) (a) Gutsche, C. D.; Gutsche, A. E.; Karaulov, A. I. J. Inclusion
Phenom. 1985, 3, 447–451. (b) Gutsche, C. D.; Bauer, L. J. J. Am. Chem.
Soc. 1985, 107, 6052–6059.
(5) (a) Sone, T.; Ohba, Y.; Moriya, K.; Kumada, H.; Ito, K. Tetrahedron
1997, 53, 10689–10698. (b) Kumagai, H.; Hasegawa, M.; Miyanari, S.;
Sugawa, Y.; Sato, Y.; Hori, T.; Ueda, S.; Kamiyama, H.; Miyano, S.
Tetrahedron Lett. 1997, 38, 3971–3972. (c) Iki, N.; Kabuto, C.; Fukushima,
T.; Kumagai, H.; Takeya, H.; Miyanari, S.; Miyashi, T.; Miyano, S.
Tetrahedron 2000, 56, 1437–1443. (d) Lhota´k, P. Eur. J. Org. Chem. 2004,
1675–1692.
(3) (a) Gutsche, C. D.; Bauer, L. J. Tetrahedron Lett. 1981, 22, 4763–
4766. (b) Gutsche, C. D. Acc. Chem. Res. 1983, 16, 161–170. (c) A related
chair-like structure has also been reported; see: Czugler, M.; Tisza, S.; Speir,
G. J. Incl. Phenom. Recognit. Chem. 1991, 11, 323–331.
10.1021/ol8028912 CCC: $40.75
Published on Web 01/16/2009
2009 American Chemical Society

homoazacalixarenes.8 Larger derivatives include octathia-
calix[8]arene,9 hexaazacalix[6]arene,10 heptaazacalix-
[7]arene,11 and octaazacalix[8]arene.12 Finally, a broad range
of heterocalixarenes incorporating alternatives to phenol
building blocks (benzene or heteroaromatic rings) linked by
methylene and/or heteroatom bridges have been described.4,13
In this paper we report on the preparation of diazacalix[8]arene
and triazacalix[12]arene methyl ethers as examples of p-tert-
butylazacalixarenes with regioselective substitution of bridg-
ing methylenes with free amino groups.
bromide 9 employing Pd2(dba)3 as the catalyst in the presence
of JohnPhos16 and t-BuONa provided diaryl amine 10 in 92%
yield. With two viable routes available to assemble model
diarylamines the stage was set to examine intramolecular
variants of these reactions to prepare azacalixarene macro-
cycles.
Scheme 1
.
Synthetic Routes toward Diarylamines Derived from
p-tert-Butylphenol
Figure 1. Heteroatom-bridged p-tert-butylcalix[4]arenes.
To investigate the effect of nitrogen bridge substitution
on the conformational properties of p-tert-butylcalixarenes,
our focus turned toward the synthesis of monoazacalix[4]arene.
To prepare azacalixarenes with only partial substitution of
bridging methylene groups with nitrogen atoms, a stepwise
approach was required as opposed to one-pot syntheses
available for symmetrical macrocycles. We envisioned
preparing monoazacalix[4]arene through an open chain linear
tetramer employing formation of an N-aryl bond as the ring-
closing step. Two intermolecular strategies were examined
to prepare diaryl amines derived from p-tert-butylphenol to
test the scope of the ring-closing step (Scheme 1). We have
previously reported on the synthesis and acid-catalyzed
condensation of N-arylhydroxylamine 6 with p-tert-butyl-
phenol to furnish diarylamine 7 in a combined two-step 60%
yield from 4-tert-butyl-2-nitroanisole 5.14 Alternatively,
Buchwald-Hartwig aryl amination15 of aniline 8 with aryl
Initial efforts to prepare monoazacalix[4]arene focused on
an intramolecular acid-catalyzed hydroxylamine condensation
on a linear tetramer (Scheme 2). This approach parallels the
syntheses of parent calixarenes employing intramolecular
acid-catalyzed condensations of monohydroxymethylated
linear tetramers originally described by Hayes and Hunter.17
Nitration of 4-tert-butyl-2-(hydroxymethyl)phenol 1118 with
cold HNO3 in benzene readily afforded nitrophenol 12 in
66% yield. Subsequent acid-catalyzed condensation with a
5-fold excess of trimer 1319 in refluxing benzene produced
nitrated tetramer 14 in 26% yield. Prior to reduction of the
nitro group to the corresponding hydroxylamine, the acidic
Scheme 2. Synthesis of Nitro-tetramer 14
(6) Ko¨nig, B.; Ro¨del, M.; Bubenitschek, P.; Jones, P. G. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 661–662.
(7) Tsue, H.; Ishibashi, K.; Takahashi, H.; Tamura, R. Org. Lett. 2005,
7, 2165–2168.
(8) Masci, B. Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield,
J., Vicens, J., Eds.; Kluwer Academic Publishers: Dordrecht, The Nether-
lands, 2001; Chapter 12, p 235.
(9) Kondo, Y.; Endo, K.; Iki, N.; Miyano, S.; Hamada, F. J. Inclusion
Phenom. 2005, 52, 45–49.
(10) Tsue, H.; Ishibashi, K.; Tokita, S.; Takahashi, H.; Matsui, K.;
Tamura, R. Chem. Eur. J. 2008, 14, 6125–6134.
(11) Tsue, H.; Matsui, K.; Ishibashi, K.; Takahashi, H.; Tokita, S.; Ono,
K.; Tamura, R. J. Org. Chem. 2008, 73, 7748–7755.
(12) Ishibashi, K.; Tsue, H.; Tokita, S.; Matsui, K.; Takahashi, H.;
Tamura, R. Org. Lett. 2006, 8, 5991–5994.
(13) Vysotsky, M.; Saadioui, M.; Bo¨hmer, V. Calixarenes 2001; Asfari,
Z.; Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer Academic
Publishers: Dordrecht, The Netherlands, 2001; Chapter 13, p 250
(14) Spence, J. D.; Raymond, A. E.; Norton, D. E. Tetrahedron Lett.
2003, 44, 849–851.
.
896
Org. Lett., Vol. 11, No. 4, 2009

Scheme 3. Intramolecular Aryl Amination Route towards p-tert-Butylazacalixarenes
phenol groups were converted to their methyl ethers by
treatment with CH3I and K2CO3 to afford 15 in 86% yield.
However, treatment of 15 with H2NNH2 and Pd/C in THF
at low temperatures, conditions developed in our model
studies, was unsuccessful in reducing the nitro group to the
corresponding hydroxylamine and afforded the fully reduced
amino product. Due to the difficulty in obtaining the labile
hydroxylamine tetramer, we turned our attention toward
palladium-catalyzed aryl amination chemistry to close the
macrocycle.
To examine an intramolecular Buchwald-Hartwig aryl
amination strategy, an open chain linear tetramer containing
the requisite amino- and bromo-substituents at opposing ends
was prepared (Scheme 3). With a rapid synthesis of nitrated
tetramer 14 in hand, the remaining free ortho-phenolic
position was brominated with Br2 in CHCl3 to afford 16 in
95% yield. To avoid competing O-arylation of the free
phenols, exhaustive methylation was accomplished with CH3I
and Cs2CO3 to afford a 66% yield of 17. Finally, selective
reduction of the nitro group in 17 with Zn in AcOH/ethanol
provided amino-bromo-derivative 18 in 91% yield. Initial
attempts at intramolecular cyclization employing Pd2(dba)3
and t-BuONa in combination with phosphine ligands BINAP,
P(tBu)3, P(Cy)3, JohnPhos, and tert-butyl JohnPhos in
refluxing toluene were unsuccessful. In each case significant
polymerization was observed with trace amounts of the
corresponding debrominated amine obtained as the only
isolable product. Upon changing the phosphine ligand to the
bulkier XPhos,20 two new products were observed whose
1H NMR spectra were greatly simplified compared to their
open chain tetramer counterparts. Upon purification NMR
andmassspectroscopyconfirmedtheformationofdiazacalix[8]arene
octamethyl ether 19 and triazacalix[12]arene dodecamethyl
ether 20 in 9.5% and 6.0% yield, respectively. Despite high
dilution techniques monoazacalix[4]arene was not observed
in the product mixture; however, ESI MS data indicated trace
amounts of the higher homologue tetraazacalix[16]arene were
produced.
The formation of azacalixarene macrocycles was con-
firmed by the relative simplicity of their 1H NMR specta in
CDCl3 (see Supporting Information). Diazacalix[8]arene 19
displayed two equally integrating tert-butyl singlets at 1.2
and 1.1 ppm along with two equally integrating methoxy
singlets at 3.45 and 3.41 ppm. Also observed were two
singlets at 4.05 and 4.02 ppm that integrated in a 2:1 ratio
for the bridging methylene groups along with four equally
integrating doublets in the aromatic region. Finally, a broad
NH singlet was observed at 6.24 ppm that is characteristic
of intramolecular bifurcated NH···OCH3 hydrogen bonding.12
The symmetry of diazacalix[8]arene 19 in solution was
further confirmed by 13C NMR spectroscopy, which dis-
played 12 aromatic resonances, two methoxy resonances, and
(15) For reviews, see: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805–818. (b) Hartwig, J. F.
Acc. Chem. Res. 1998, 31, 852–860.
(16) 2-(Di-tert-butylphosphino)biphenyl. Aranyos, A.; Old, D. W.;
Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 4369–4378.
(17) (a) Hayes, B. T.; Hunter, R. F. Chem. Ind. 1956, 193–194. (b)
Hayes, B. T.; Hunter, R. F. J. Appl. Chem. 1958, 8, 743–748.
(18) Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G. Synthesis 1980,
124–125.
(20) 2-Dicyclohexylphosphino-2′,4′,6′-tri-isopropylbiphenyl. Huang, X.;
Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 6653–6655.
(19) Dhawan, B.; Gutsche, C. D. J. Org. Chem. 1983, 48, 1536–1539.
Org. Lett., Vol. 11, No. 4, 2009
897

four tert-butyl resonances confirming the presence of two
distinct aromatic rings. In addition, two resonances were
observed at 30 ppm for the two unique methylene bridge
carbons. Triazacalix[12]arene 20 displayed a similar 1H NMR
spectrum with downfield shifts for the methoxy resonances
(3.60 and 3.58 ppm) and the NH singlet (6.38 ppm)
compared to diazacalix[8]arene 19. Ultimate verification of
the macrocycle size was obtained by mass spectrometry data.
Diazacalix[8]arene 19 gave a monocharged [M + Na]+
molecular ion peak at m/z 1433.9407 (∆ 0.3 ppm) along with
a double-charged [M + 2Na]2+ ion at m/z 728.4656 (∆ 0.1
ppm) by high resolution ESI MS. In comparison, triazacalix-
[12]arene 20 displayed an M+ peak at m/z 2116 by MALDI,
and ESI gave an [M + 2Na]2+ peak at m/z 1081.7008 (∆
3.4 ppm).
temperatures with competing de-tert-butylation upon warm-
ing to room temperature as observed in our model studies.14
In conclusion, we have developed an intramolecular
Buchwald-Hartwig aryl amination strategy to prepare p-tert-
butylazacalixarene macrocycles with selective substitution
of bridging methylenes with free amino groups. Cyclization
of amino-bromo open-chain tetramer 18 affords diazacalix[8]-
arene 19 and triazacalix[12]arene 20 methyl ethers in a
combined 15.5% yield. Although larger macrocycles are
observed by mass spectroscopy, no evidence of the mono-
meric azacalix[4]arene was noted. Studies to examine the
effect of selective NH bridge substitution on the conforma-
tional properties of azacalixarenes are currently ongoing
along with continued efforts to prepare monoazacalix[4], [5]
and [6]arenes through intramolecular aryl amination strate-
gies.
1
Dynamic H NMR studies of diazacalix[8]arene 19 over
the temperature range 213-333 K displayed only slight
broadening of the bridging methylene singlets at low
temperature, indicating that the macrocycle remains confor-
mationally mobile as observed for the parent p-tert-
butylcalix[8]arene methyl ether.21 To date, efforts to obtain
suitable crystals to examine solid-state conformation have
been unsuccessful. Attempts to exhaustively demethylate 19
by treatment with BBr3 to examine conformational properties
of the free phenol led to incomplete demethylation at low
Acknowledgment. This work was funded by grants from
the American Chemical Society Petroleum Research Fund
(Grant 37948-GB1) and the California State University,
Sacramento, Research and Creative Activity Award Program.
Supporting Information Available: Full experimental
procedures and spectroscopic data for compounds 12, 14,
and 16-20. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Gutsche, C. D.; Bauer, L. J. J. Am. Chem. Soc. 1985, 107, 6059–
6063.
OL8028912
898
Org. Lett., Vol. 11, No. 4, 2009