First protection of a wide-rim tetraamino calix[4]arene in opposite positions

Article abstract of DOI:10.1021/ol062943s

(Chemical Equation Presented) The importance of tetraamino calix[4]arenes as starting materials is distinctly increased by the first versatile protective group for opposite amino functions. Reaction with trityl chloride leads to the 1,3-dialkylated deriva

Full text of DOI:10.1021/ol062943s

ORGANIC
LETTERS
2007
Vol. 9, No. 6
957-960
First Protection of a Wide-Rim
Tetraamino Calix[4]arene in Opposite
Positions
Yuliya Rudzevich,*,† Valentyn Rudzevich,†,‡ Dieter Schollmeyer,§ and
Volker Bo1
hmer*,†
Abteilung Lehramt Chemie, Fachbereich Chemie, Pharmazie und Geowissenschaften,
Johannes Gutenberg-UniVersita¨t Mainz, Duesbergweg 10-14, D-55099 Mainz,
Germany, and Institut fu¨r Organische Chemie, Johannes Gutenberg-UniVersita¨t Mainz,
Duesbergweg 10-14, D-55099 Mainz, Germany
rudzeVic@uni-mainz.de; Vboehmer@uni-mainz.de
Received December 5, 2006
ABSTRACT
The importance of tetraamino calix[4]arenes as starting materials is distinctly increased by the first versatile protective group for opposite
amino functions. Reaction with trityl chloride leads to the 1,3-dialkylated derivative easily isolated in 34% yield; after a first acylation of the
remaining amino groups, the trityl residues can be removed by TFA to introduce a second acyl group.
Wide-rim tetraamino calix[4]arenes are rather interesting and
useful macrocyclic compounds. They are easily available in
large quantities1 and serve as attractive starting material for
various fascinating structures. Extractants for lanthanides and
actinides,2 different anion receptors,3 intriguing self-as-
sembled structures,4,5 sophisticated rotaxanes and catenanes,6
and building blocks for self-assembled dendrimers7 were
prepared starting from tetraamino calix[4]arenes.
In some cases, the combination of (different) functional
groups is very important. For example, the introduction of
(3) For a recent review, see: Matthews, S. E.; Beer, P. D. In Calixarenes
2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer
Academic Publishers: Dordrecht, 2001; Chapter 23, pp 421-439. For some
selected examples, see: Dudicˇ, M.; Lhota´k, P.; Stibor, I.; Lang, K.;
Prosˇkova´, P. Org. Lett. 2003, 5, 149-152. Casnati, A.; Massera, C.; Pelizzi,
N.; Stibor, I.; Pinkassik, E.; Ugozzoli, F.; Ungaro, R. Tetrahedron Lett.
2002, 43, 7311-7314. Sansone, F.; Baldini, L.; Casnati, A.; Lazzarotto,
M.; Ugozzoli, F.; Ungaro, R. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4842-
4847. Morzherin, Y.; Rudkevich, D. M.; Verboom, W.; Reinhoudt, D. N.
J. Org. Chem. 1993, 58, 7602-7605.
† Abteilung Lehramt Chemie, Fachbereich Chemie, Pharmazie und
Geowissenschaften, J. G.-Universita¨t Mainz.
‡ Permanent address: Institute of Organic Chemistry, NAS of Ukraine,
Murmanska str. 5, 02094, Kyiv-94, Ukraine.
(4) For a short review, see: Rebek, J., Jr., Chem. Commun. 2000, 637-
643. For some selected examples, see: Castellano, R. K.; Rebek, J., Jr. J.
Am. Chem. Soc. 1998, 120, 3657-3663. Brody, M. S.; Schalley, C. A.;
Rudkevich, D. M.; Rebek, J., Jr. Angew. Chem., Int. Ed. 1999, 38, 1640-
1644. Pop, A.; Vysotsky, M. O.; Saadioui, M.; Bo¨hmer, V. Chem. Commun.
2003, 1124-1125. Rudzevich, Y.; Fischer, K.; Schmidt, M.; Bo¨hmer, V.
Org. Biomol. Chem. 2005, 3, 3916-3925.
§ Institut fu¨r Organische Chemie, J. G.-Universita¨t Mainz.
(1) Ipso-nitration of tetraethers of calix[4]arene followed by catalytic
hydrogenation affords respective tetraamines in high yields. See: Verboom,
W.; Durie, A.; Egberink, R. J. M.; Asfari, Z.; Reinhoudt, D. N. J. Org.
Chem. 1992, 57, 1313-1316. Jakobi, R. A.; Bo¨hmer, V.; Gru¨ttner, C.; Kraft,
D.; Vogt, W. New J. Chem. 1996, 20, 493-501.
(2) Delmau, L. H.; Simon, N.; Schwing-Weill, M.-J.; Arnaud-Neu, F.;
Dozol, J.-F.; Eymard, S.; Tournois, B.; Bo¨hmer, V.; Gru¨ttner, C.; Musig-
mann, C.; Tunayar, A. Chem. Commun. 1998, 1627-1628. Delmau, L. H.;
Simon, N.; Schwing-Weill, M.-J.; Arnaud-Neu, F.; Dozol, J.-F.; Eymard,
S.; Tournois, B.; Gru¨ttner, C.; Musigmann, C.; Tunayar, A.; Bo¨hmer, V.
Sep. Sci. Technol. 1999, 34, 863-876.
(5) Shivanyuk, A.; Saadioui, M.; Broda, F.; Thondorf, I.; Vysotsky, M.
O.; Rissanen, K.; Kolehmainen, E.; Bo¨hmer, V. Chem.-Eur. J. 2004, 10,
2138-2148.
(6) For a recent review, see: Bogdan, A.; Rudzevich, Y.; Vysotsky, M.
O.; Bo¨hmer, V. Chem. Commun. 2006, 2941-2952.
(7) Rudzevich, Y.; Rudzevich, V.; Moon, C.; Schnell, I.; Fischer, K.;
Bo¨hmer, V. J. Am. Chem. Soc. 2005, 127, 14168-14169.
10.1021/ol062943s CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/13/2007

several ligating functions at well-defined positions can
significantly influence selectivity or effectivity of extract-
ants.8 Also, the well-known dimerization of the tetraurea
calix[4]arene does not occur if just one urea group is replaced
by an acetamide function; instead, an astonishing tetrameric
assembly with a totally different hydrogen-bonding pattern
is formed.5 Novel catenanes with different sizes of the loops
are also worth being mentioned.9
Scheme 1. Synthesis of a Tetraacyl Calix[4]arene Bearing
Two Different Acyl Groups in Alternating Order
The controlled synthesis of such intriguing compounds is
strongly facilitated by the selective protection of amino func-
tions. Although simple and effective procedures for mono-
Boc (36%), 1,2-di-Boc (48%), and tri-Boc (54%) protection
were formerly developed, the 1,3-di-Boc-substituted deriva-
tive was not even detected.10 However, calixarenes possessing
two different acyl residues in alternating order are often the
most interesting examples due to their higher symmetry. The
dimerization of tetraurea derivatives with alternating urea
functions (ABAB), for instance, leads to a single regioisomer
with supramolecular chirality, whereas two regioisomeric
dimers are formed from an AABB isomer.11
Two different strategies were proposed for the synthesis
of precursors possessing two nitro and two amino groups in
alternating order.12 Both ways comprise seven steps, each
starting from the parent calix[4]arene, and afford the target
products in 8-20% overall yield. Thus, the synthesis of 1,3-
diprotected tetraamino calix[4]arenes remains quite compli-
cated and the corresponding derivatives are almost not
studied. Therefore, a direct selective protection is still of great
interest.
Neither concentration nor the alkylating agent significantly
influenced the yield of the 1,3-dialkylated compound and
the ratio between the products. A slow addition of trityl
chloride was also not important because similar yields were
obtained when the reagents were rapidly mixed. Obviously,
the substitution occurs statistically and not selectively.
Remarkable differences were observed when the alkylation
was carried out without triethylamine. Only mono-15 and
disubstituted derivatives were observed by TLC in the
reaction mixture, whereas all possible alkylation products
were formed in the presence of triethylamine.
Thus, to reduce the amount of the tetra- and trialkylated
products, the trityl chloride was added to the substrate in
two portions. The first 2.2 mol of alkylating agent was
reacted with the tetraamine, also used as base. Subsequently,
the triethylamine and the extra portion of trityl chloride (1.1
mol) were added. This sequence afforded the 1,3-disubsti-
tuted compound which crystallized in 34% yield from the
reaction mixture.16
Mono-, tri-, and tetrasubstituted derivatives were also
separated and characterized, but their yields were not
optimized because analogous derivatives are easily obtained
by Boc protection.10 Complete deprotection of this mixture
allowed recovery of 56% of the tetraamino calix[4]arene
1.16,17 Thus, only 10% of the starting material was lost.
The remaining amino groups were easily acylated with
tolyl isocyanate or with acetic acid anhydride. As expected,
the cleavage of the trityl groups with TFA in dichloromethane
occurs selectively, leading to 1,3-disubstituted diaminocalix-
[4]arenes 4 in 90-95% yields. Acylation of the last two
amino groups gives product 5 (as an example) bearing two
different acyl groups in alternating order.
The absence of 1,3-diacylation products can be explained
by the formation of a trans-cavity hydrogen bond13 between
the first amide function and the opposite amino group, which
is thus deactivated. This observation suggests that in alkylated
amines such hindrance should be absent.
On the basis of these considerations, we have tried to
attach triphenylmethyl as a protecting group by direct 1,3-
dialkylation of the tetraamino calix[4]arene under the fol-
lowing conditions (Scheme 1). Two equivalents of trityl
chloride were added dropwise to the chloroform solution of
1 (c ) 1 g/L) in the presence of triethylamine. Indeed, the
1
target product was detected by H NMR and it was easily
separated from the mixture of all possible derivatives by a
simple crystallization in ∼20% yield.
To optimize the reaction conditions, the alkylation was
carried out at different concentrations (1-10 g/L) of starting
calix[4]arene 1 using trityl chloride or trityl bromide.14
(8) For a recent example at the narrow rim, see: Mikula´sˇek, L.; Gru¨ner,
B.; Danila, C.; Bo¨hmer, V.; Ca´slavsky´, J.; Selucky´, P. Chem. Commun.
2006, 4001-4003.
(9) Molokanova, O.; Bogdan, A.; Vysotsky, M. O.; Bolte, M.; Ikai, T.;
Okamoto, Y.; Bo¨hmer, V., manuscript in preparation.
(10) Saadioui, M.; Shivanyuk, A.; Bo¨hmer, V.; Vogt, W. J. Org. Chem.
1999, 64, 3774-3777.
The structures of all products were unambiguously proved
1
by H and 13C NMR spectroscopy and mass spectrometry.
(11) See: Pop, A.; Vysotsky, M. O.; Saadioui, M.; Bo¨hmer, V. Chem.
Commun. 2003, 1124-1125.
(12) Bogdan, A.; Vysotsky, M. O.; Bo¨hmer, V. Collect. Czech. Chem.
Commun. 2004, 69, 1009-1026. van Wageningen, A. M. A.; Timmerman,
P.; van Duynhoven, J. P. M.; Verboom, W.; van Veggel, F. C. J. M.;
Reinhoudt, D. N. Chem.-Eur. J. 1997, 3, 639-654.
(13) Scheerder, J.; Vreekamp, R. H.; Engbersen, J. F. J.; Verboom, W.;
van Duynhoven, J. P. M.; Reinhoudt, D. N. J. Org. Chem. 1996, 61, 3476-
3481.
(14) Because of its hygroscopic properties, trityl bromide should be
freshly opened or dried.
(15) Trityl chloride is partly hydrolyzed to the trityl alcohol during the
reaction. As an example, see: Canle, M. L.; Clegg, W.; Demirtas, I.;
Elsegood, M. R. J.; Haider, J.; Maskill, H.; Miatt, P. C. J. Chem. Soc.,
Perkin Trans. 2 2001, 1742-1747.
958
Org. Lett., Vol. 9, No. 6, 2007

Colorless crystals of 3b suitable for X-ray crystallographic
analysis18 were obtained by slow crystallization from DMSO.
The asymmetric unit comprises two calixarenes and six
molecules of DMSO. One of the urea fragments of each
calixarene forms bifurcated hydrogen bonds with the oxygen
of a single DMSO, whereas the second urea group is bound
to the two solvent molecules. The calixarene assumes the
pinched cone conformation (Figure 2), in which surprisingly
1
Figure 1. Sections of the H NMR spectra of 2 (a), mono- (b),
and trisubstituted (c) tetraamino calix[4]arenes proving the absence
of other alkylation products in 2.
1
The H NMR spectrum of compound 2 (Figure 1) contains
two singlets for the aromatic protons of the calixarene
skeleton, one singlet for NH, and one pair of doublets for
the protons of the methylene bridges showing the expected
pattern for a molecule of the ABAB type.
Figure 2. Molecular conformation of compound 3b seen from the
side (top) and from the top (bottom). Hydrogen atoms, pentyl
substituents, and solvent molecules are omitted for clarity.
(16) Synthesis of 2: A solution of triphenylmethyl chloride (1.6 g, 5.75
mmol) in chloroform (50 ml) was added in one portion (fast) to the
vigorously stirred solution of tetraamino calix[4]arene 1 (2.0 g, 2.61 mmol)
in chloroform (100 ml). After 6 h, triethylamine (2.9 mL, 20.91 mmol)
was added to the reaction mixture, and after the next 2 h, the second portion
of triphenylmethyl chloride (0.73 g, 2.61 mmol) in chloroform (50 mL)
was added. Stirring was continued for 6 h, and the solvent was removed
under reduced pressure. The residue was dissolved in chloroform (100 ml),
washed with water, and dried over MgSO4. After evaporation, the residue
was dissolved in the mixture of diethyl ether (7 ml) and hexane (10 ml)
and kept at -14 °C. The formed precipitate was filtered off, washed with
a cold mixture of diethyl ether/hexane (1:1), and dried on the air to give
compound 2 (1.1 g, 34 %), mp 162-164 °C: 1H NMR (400 MHz, CDCl3),
the phenolic rings bearing bulky trityl substituents are almost
parallel (the shortest distance between the closest carbons
of the opposite trityl groups is 3.6 Å). The patch angles of
two opposite trityl- and tolyl-substituted aromatic units to
the reference plane passing through the methylene bridges
are 84.5 ( 0.6 and 127.5 ( 0.8°, respectively. Some other
typical angles and distances are shown in Table 1.
δ
H 0.889 (t, 6H, 3J ) 7.0 Hz, CH3), 0.894 (t, 6H, 3J ) 7.0 Hz, CH3), 1.07-
1.48 (m, 16H, CH2), 1.65-1.83 (m, 8H, CH2), 2.60 (d, 4H, 2J ) 13.2 Hz,
In conclusion, the first preparatively useful procedure for
the direct protection of a wide-rim tetraamino calix[4]arene
at opposite positions was elaborated. The facile synthesis
and the simple purification allow us to obtain the target
compound on a multigram scale. It was also shown that the
further functionalization of the remaining amino groups, the
ArCH2Ar), 2.78 (br s, 4H, NH2), 3.45 (t, 4H, 3J ) 6.4 Hz, OCH2), 3.78
(m, 4H, OCH2), 4.10 (d, 4H, J ) 13.2 Hz, ArCH2Ar), 4.74 (s, 2H, NH),
2
4.87 (s, 4H, ArH), 6.11 (s, 4H, ArH), 7.2-7.5 (m, 30H, PhH); 13C{1H}
NMR (100.6 MHz, CDCl3), δC 14.0 (s, CH3), 14.3 (s, CH3), 22.7 (s, CH2),
22.9 (s, CH2), 28.1 (s, CH2), 28.7 (s, CH2), 29.5 (s, CH2), 30.1 (s, CH2),
31.1 (s, CH2), 72.0 (s, CPh3), 74.7 (s, OCH2), 74.9 (s, OCH2), 114.8 (s,
CHAr), 117.5 (s, CHAr), 126.5 (s, CHAr), 127.8 (s, CHPh), 129.4 (s, CHPh),
133.6 (s, CAr), 136.6 (s, CPh), 140.1 (s, CAr), 140.4 (s, CAr), 146.1 (s, CPh),
148.9 (s, CAr), 150.6 (s, CAr); m/z (FD) 1248.8 (100) [M]+, 1006.7 (30) [M
- Ph3C]+, calcd 1249.75. The mother solution was evaporated. Its
deprotection (see below) afforded 1.12 g (56 %) of the starting tetraamino
calix[4]arene 1.
(18) Crystal data for 3b: C102H106N6O6 × 3SO(CH3)2, M ) 1746.31,
triclinic, a ) 16.6852(5) Å, b ) 18.6076(6) Å, c ) 19.9047(6) Å, R )
99.238(1)°, â ) 112.682(1)°, γ ) 113.338(1)°, V ) 4864.2(3) Å3, T )
183 K, space group P-1 (No. 2), Z ) 2, µ(Mo KR) ) 0.14 mm-1, 33 300
reflection measured, 21 641 unique (Rint ) 0.0360) which were used in all
(17) General procedure for the cleavage of the trityl groups: The trityl-
containing compound was dissolved in methylene chloride. After addition
of trifluoroacetic acid (10 mol per group), the mixture was stirred for 2 h.
The solvent and acid were removed under reduced pressure. The residue
was dissolved in chloroform, washed with an aqueous solution of K2CO3
(10 %) and water, and dried over MgSO4. Precipitation with hexane or
Et2O from the chloroform solution leads to product 4 (80-85 %).
calculations. The final wR(F2) was 0.35 (all data). ∆Fmax ) 1.93 eÅ-3
.
The crystals obtained from 3b had very low reflecting power at higher
diffraction angles. The whole structure is highly disordered due to the
included solvent molecules and to the pentyl chains. Therefore, the R values
are rather high, but the molecular structure is proved nevertheless.
Org. Lett., Vol. 9, No. 6, 2007
959

wide possibilities for the preparation and investigation of
calix[4]arenes bearing different N-acyl groups in alternat-
ing order and closes a significant gap in the synthetic
repertoire.
Table 1. Selected Geometric Parameters of 3b
parameter
value
angles (°)a
ArTol / ArTol
ArTrt / ArTrt
MPb / ArTol
74.95
11.07
126.72/128.23
83.92/85.10
Acknowledgment. We gratefully acknowledge financial
support from the Deutsche Forschungsgemeinschaft (Bo 523/
14-4, SFB 625). We thank Dr. H. Go¨rls (Institute of
Inorganic and Analytical Chemistry, Friedrich Schiller
University Jena) for the collection of X-ray data of compound
3b.
MPb / ArTrt
distances (Å)
(O)CTol-(O)CTol
(N)CTol-(N)CTol
(O)CTrt-(O)CTrt
(N)CTrt-(N)CTrt
c
5.48
9.87
5.37
4.81
d
c
d
a Ar: aromatic rings of the calixarene skeleton. bMP: plain passing
Supporting Information Available: 1H and 13C NMR
spectra of synthesized compounds and crystallographic
details for 3b. This material is available free of charge via
the Internet at http://pubs.acs.org.
c
through the methylene bridges of the calixarene skeleton. (O)C: carbon
atom to which the alkoxy residue is attached. d(N)C: carbon atom to which
the urea/trityl is attached.
following deprotection, and exhaustive acylation occur
selectively and in high yields. This reaction sequence opens
OL062943S
960
Org. Lett., Vol. 9, No. 6, 2007