Selective functionalization at the small rim of calix[6]arene. Synthesis of novel non-symmetrical N3, N4 and N3ArO biomimetic ligands

Article abstract of DOI:10.1016/S0040-4020(03)00780-4

Eight novel calix[6]arene-based biomimetic ligands for transition metal ions have been synthesized. They display a non-symmetrical N₃, N₄ or N₃ArO binding core that mimics enzyme active sites presenting histidine and tyrosine residues. The key step for their synthesis is the mono-alkylation at the small rim of the C_3v symmetrical trimethyl ether derivative of tBu-calix[6]arene with N-Boc-2-chloroethylamine to yield a novel calix[6]arene synthon. Its combined O-alkylation with a chloromethyl aromatic amine and N-deprotection or alkylation or reductive alkylation with a salicylaldehyde derivative yielded the calix[6]arene-based ligands with mixed N/O donors.

Full text of DOI:10.1016/S0040-4020(03)00780-4

Tetrahedron 59 (2003) 5563–5568
Selective functionalization at the small rim of calix[6]arene.
Synthesis of novel non-symmetrical N3, N4 and
N3ArO biomimetic ligands
*
´ `
Olivier Seneque and Olivia Reinaud
´ ´
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR CNRS 8601, Universite Rene Descartes,
`
45 rue des Saints-Peres, 75270 Paris cedex 06, France
Received 10 March 2003; accepted 20 May 2003
Abstract—Eight novel calix[6]arene-based biomimetic ligands for transition metal ions have been synthesized. They display a non-
symmetrical N3, N4 or N3ArO binding core that mimics enzyme active sites presenting histidine and tyrosine residues. The key step for their
synthesis is the mono-alkylation at the small rim of the C3v symmetrical trimethyl ether derivative of tBu-calix[6]arene with N-Boc-2-
chloroethylamine to yield a novel calix[6]arene synthon. Its combined O-alkylation with a chloromethyl aromatic amine and N-deprotection
or alkylation or reductive alkylation with a salicylaldehyde derivative yielded the calix[6]arene-based ligands with mixed N/O donors. q 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
trimethylether of tBu-calix[6]arene X6Me3H3 using various
alkyl chloride (2-chloromethyl-N-methylimidazole,
2-chloromethyl-N-methylbezimidazole, N-chloromethyl-
pyrazole, 2-chloromethylpyridine, N,N-dimethyl-2-chloro-
ethylamine) in the presence of excess NaH1,4 or K2CO3,2 in
THF/DMF or DMF, respectively. When the calixarene was
reacted with only a stoichiometric amount of the above-
mentioned alkylating agent and/or base, the tris(alkylated)
compound X6Me3N3 remained by far the major product and
a sizeable part of X6Me3H3 was recovered. The mono- and
di-alkylated products were formed only in very small
amounts.
We are involved in a research program devoted to the
modeling of metallo-enzyme active sites with supra-
molecular systems. In the recent years, we have shown
that calix[6]arenes can be used as a platform for the
preorganization of a metal ion binding site in close
proximity of a hydrophobic cavity. For that purpose,
selective alternate alkylation of three out of the six phenolic
units of the calix[6]arene was the key step for obtaining a
variety of C3v symmetrical N3 ligands.1,2 Because of the
great diversity of metallo-enzyme active sites, we were
interested in developing a novel synthetic strategy allowing
the disymetrisation of the calix[6]arene-based system.3
Therefore, we explored the selective functionalization of the
C3v tris(methylated)calixarene X6Me3H3 and found a novel
procedure giving rise to its monoalkylation with an amino-
protected group. This key step allowed us to synthesize
within 3 or 4 steps starting from X6Me3H3 non-symmetrical
N3, N4 and N3ArO ligands.
In strong contrast with these results, when the Boc-protected
chloroethylamine was used as an electrophilic agent,
partially alkylated compounds were obtained as major
products and peralkylation of X6Me3H3 revealed itself to be
a minor process. Thus, optimization of the reaction
conditions, thanks to a careful control of both the reaction
conditions and the relative stoichiometric quantities of each
reagent, led to an efficient procedure for the preparation of a
novel non-symmetrical calix[6]arene synthon. When
X6Me3H3 was reacted with ClCH2CH2NHBoc5 (5 equiv.)
and NaH (3.2 equiv.) in a THF/DMF 5:1 mixture,
calix[6]arene X6Me3H2(NHBoc) was obtained with a 75%
yield based on converted X6Me3H3 (Scheme 1). Column
chromatography allowed its separation from the di-alkyl-
ated product X6Me3H(NHBoc)2 and the tri-alkylated
product X6Me3H(NHBoc)3 (identified by ES-MS) that
were formed in only small amounts. The 1H NMR spectrum
of X6Me3H2(NHBoc) is characteristic of a Cs-symmetrical
species with the methoxy groups rejected out of the
calixarene cavity (dOMe¼3.40 and 3.88 ppm) and the
2. Results
2.1. Selective functionalization of calix[6]arene X6Me3H3
The synthesis of C3v symmetric N3 calix[6]arene-based
ligands were achieved by per-alkylation of the 1,3,5-
Keywords: calix[6]arene; selective alkylation; biomimetic; mixed N/O-
ligand.
*
Corresponding author. Tel.: þ33-1-42862183; fax: þ33-1-42868387;
e-mail: reinaud@biomedicale.univ-paris5.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00780-4

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O. Seneque, O. Reinaud / Tetrahedron 59 (2003) 5563–5568
5564
Scheme 1. Selective functionalization of X6Me3H3. Conditions: NaH (3.2 equiv.), ClCH2CH2NHBoc (5 equiv.), THF/DMF 4:1, reflux, 6 h.
OC2H4NHBoc arm partially included in the p-basic cavity
opposite of what was observed for the tri-alkylated N3
products.1
(dOCH ¼2.55 ppm). The 13C NMR resonances for the
2
bridging methylene (dArCH2Ar<29–32 ppm)6 and a
ROESY experiment confirmed that this new compound
actually adopts a flattened cone conformation where the
relative in and out positions of the phenolic units are the
2.2. Non-symmetrical N3 and N4 ligands
Preparation of the non-symmetrical N3 ligand
Scheme 2. Synthesis of N3 and N4 ligands. Conditions: (i) NaH (4.55 equiv.), 2-chloromethyl-1-methylimidazole hydrochloride (2.5 equiv.), THF/DMF 5:1,
reflux, 3 h; (ii) K2CO3 (16 equiv.), 2-chloromethylpyridine hydrochloride (6.3 equiv.), DMF, 1508C, 5 h; (iii) CHCl3/CF3COOH 5:1, 258C, 1 h; (iv) NaH
(15 equiv.), 2-chloromethyl-1-methylimidazole hydrochloride (5 equiv.), THF/DMF 4:1, reflux, 5 h; (v) CHCl3/CF3COOH 20:1, 258C, 3 h.

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O. Seneque, O. Reinaud / Tetrahedron 59 (2003) 5563–5568
5565
1
X6Me3Imme2NH2, bearing one aliphatic primary amine and
two imidazole moieties, was achieved by reacting X6Me3-
H2(NHBoc) in a THF/DMF mixture with 2-chloromethyl-1-
methylimidazole hydrochloride (2.5 equiv.) and NaH
(4.55 equiv.).7 The pyridine analog X6Me3Pic2NH2 was
synthesized in DMF with 2-chloromethylpyridine hydro-
chloride and K2CO3 in excess as a base instead of NaH.8
After treatment with trifluoroacetic acid, X6Me3Imme2NH2
and X6Me3Pic2NH2 were obtained in 83 and 63% yields,
respectively (Scheme 2).
The H NMR spectra of all these new ligands present a
classical flattened Cs cone conformation with their methoxy
groups folded into the p-basic cavity.
3. Discussion–conclusion
Whereas the reaction of X6Me3H3 with various alkyl
chlorides bearing amino groups yielded the tris-alkylated
compound as a major product, it was possible to implement
selective mono-alkylation with an aminoethyl group
protected as a carbamate. According to our experiments, it
seems likely that per-alkylation of X6Me3H3 undergoes a
cooperative process, whereby the introduction of a second
then a third basic group (i.e. an amine) on the calixarene
skeleton is due to auto-catalysis. Masking the basicity of the
amino arm with a sterically encumbered Boc protecting
group may well be the key for the exceptional selectivity
observed for the mono-alkylation with the chloroethylamine
derivative. The mono-alkylated calix[6]arene X6Me3H2-
(NHBoc) revealed to be a key synthon. Indeed, it can be
further functionalized on the phenol and/or the amino
moieties. This allowed us to synthesize a new set of non-
symmetrical N3, N4 and N3ArO calix[6]arene-based ligands,
that can closely mimic the coordination sphere found in
some enzymes. For example, the N3ArO ligands now
present a phenol group that can model the tyrosine residue
encountered in galactose oxidase.10 The various donor
strength and steric hindrance provided by this novel family
of biomimetic ligands should also allow the tuning of the
properties of the corresponding metal complexes.
Reaction of X6Me3H2(NHBoc) with an excess of 2-chloro-
methyl-1-methylimidazole hydrochloride and NaH in a
THF/DMF mixture led to the alkylation of both phenolic
functions and the NHBoc moiety. After treatment with
trifluoroacetic acid new compound X6Me3Imme2NHImme
was obtained in 91% yield (Scheme 2).
2.3. N3ArO ligands
A family of N3ArO ligands were prepared by reductive
amination of X6Me3Imme2NH2 and X6Me3Pic2NH2 using
various salicylaldehydes and NaBH4 as the reducing agent
in EtOH. Ligands X6Me3Imme2NHArR,R OH and X6Me3-
0
Pic2NHArtBu OH were obtained in 50–76% yield according
2
to Scheme 3. Finally, a ligand presenting a tertiary amine
moiety in place of the secondary amine function was
synthesized.9 Indeed, X6Me3Imme2NHArtBu OH was quan-
2
titatively converted into X6Me3Imme2NPrArtBu OH, bear-
2
ing a N-propyl amino-phenol arm, by reductive amination
using EtCHO and NaBH3CN in EtOH.
Scheme 3. Synthesis of N3O ligands. Conditions: (i) 2-hydroxy-3-R0-5-R-benzaldehyde (excess), EtOH, 258C, 1 h, NaBH4 (excess), 258C, 1 h; (ii) EtCHO
(6 equiv.), NaBH3CN (2 equiv.), EtOH, 258C, 1 h.

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O. Seneque, O. Reinaud / Tetrahedron 59 (2003) 5563–5568
5566
Complexation studies with these ligands will be reported
elsewhere.
145.8 (CAr), 147.2 (CAr), 150.6 (CArO), 151.3 (CArO), 153.2
(CArO), 153.3 (CArO), 156.7 (CvO). Anal. calcd for
C76H103NO8: C 78.78, H 8.96, N 1.21; found C 78.74, H
9.01, N 1.18.
4. Experimental
4.1. General
4.1.2. 5,11,17,23,29,35-Hexa-tert-butyl-37,39,41-tri-
methoxy-38-[2-(amino)ethoxy]-40,42-bis[(1-methyl-2-
imidazolyl)methoxy]calix[6]arene (X6Me3Imme2NH2).
Under an argon atmosphere, 2-chloromethyl-1-methylimi-
dazole hydrochloride12 (505 mg, 3.02 mmol) was intro-
duced into a solution of X6Me3H2(NHBoc) (1.40 g,
1.21 mmol) in THF (60 mL). NaH (60% in oil, 220 mg,
5.5 mmol) and DMF (12 mL) were added to the reaction
mixture. After 3 h on refluxing, the solvent were concen-
trated under reduced pressure to a quarter of the volume and
water (100 mL) was poured into the solution. The resulting
precipitate was collected by filtration and dissolved in
CH2Cl2. The organic layer was washed with water, dried
(Na2SO4) and evaporated under reduced pressure. The
residue was dissolved in a CHCl3/CF3COOH 5:1 mixture
(12 mL). The solution was stirred for 1.5 h and evaporated
under reduced pressure. The oily residue was dissolved in
CH2Cl2. The organic layer was washed with 1N NaOH,
dried (Na2SO4) and evaporated under reduced pressure.
Recrystallization in CH2Cl2/CH3CN yielded X6Me3Imme2-
NH2 as a white powder (1.1 g). Yield: 83%. Mp: 1778C. IR
(KBr): n¼1500, 1481, 1479, 1468, 1465, 1454, 1414, 1392,
1362, 1292, 1285, 1245 cm21. 1H NMR (250 MHz, CDCl3):
d¼0.82 (s, 27H, tBu), 1.34 (s, 18H, tBu), 1.37 (s, 9H, tBu),
2.14 (s, 3H, OCH3), 2.31 (s, 6H, OCH3), 2.99 (br t, 2H,
NCH2CH2O), 3.23 (d, J¼14.8 Hz, 2H, Ar-aCHeq), 3.27 (d,
J¼14.8 Hz, 2H, Ar-aCHeq), 3.50 (d, J¼14.8 Hz, 2H,
Ar-aCHeq), 3.77 (br t, 2H, OCH2CH2N), 3.88 (s, 6H,
NCH3), 4.3–4.5 (m, 6H, Ar-aCHax), 5.02 (s, 4H, OCH2Im),
6.66 (s, 2H, ArH), 6.68 (s, 4H, ArH), 6.91 (s, 2H, ImH), 6.99
(s, 2H, ImH), 7.20 (s, 2H, ArH), 7.23 (s, 2H, ArH). Anal.
calcd for C81H111N5O8·2H2O C 75.84, H 8.72, N 5.46;
found C 75.74, H 8.74, N 5.54.
All solvents and reagents were obtained commercially.
˚
DMF was stored over 4 A molecular sieves under argon.
THF was distilled under argon over sodium/benzophenone.
1H and 13C NMR spectra were recorded on Bruker Avance
400 and Bruker ARX 250 spectrometers. 1H and 13C
resonances corresponding to anisole moieties are noted 1
(e.g. tBu1, ArH1, CA1 r) and the others are noted 2. They were
assigned with HMBC and HMQC experiments. IR spectra
were recorded on a Perkin–Elmer 783 spectrometer.
Elemental analyses were performed at the Institut de
Chimie des Substances Naturelles, France.
4.1.1. 5,11,17,23,29,35-Hexa-tert-butyl-37,39,41-tri-
methoxy-38-[2-[[(tert-butyloxy)carbonyl]-amino]-
ethoxy]-calix[6]arene-40,42-diol
[X6Me3H2(NHBoc)].
Under an argon atmosphere, NaH (60% in oil, 252 mg,
6.3 mmol) and DMF (20 mL) were added to a solution of
X6Me3H3 (5,11,17,23,29,35-hexa-tert-butyl-37,39,41-tri-
methoxycalix[6]arene-38,40,42-triol)11 (2.0 g, 1.97 mmol)
in THF (80 mL). The reaction mixture was stirred for
30 min at room temperature and ClCH2CH2NHBoc5
(1.77 g, 9.8 mmol) was introduced. After 6 h of refluxing,
the solvent was concentrated under reduced pressure to a
quarter of the volume and water (100 mL) was poured into
the solution. The resulting precipitate was collected by
filtration and dissolved in CH2Cl2. The organic layer was
washed with water, dried (Na2SO4) and evaporated under
reduced pressure. Pentane was added to the yellow residue.
A white precipitate of non converted X6Me3H3 appeared
and was filtered off. The filtrate was evaporated under
reduced pressure. Column chromatography on silica gel
using CH2Cl2/AcOEt 97:3 as the eluent yielded X6Me3H2-
(NHBoc) as a white powder (1.42 g). Yield: 75% (based on
82% converted X6Me3H3). Mp: 1658C. IR (KBr): n¼1720
(CvO), 1535, 1515, 1488, 1440, 1420, 1398, 1365, 1295,
4.1.3. 5,11,17,23,29,35-Hexa-tert-butyl-37,39,41-tri-
methoxy-38-[2-(amino)ethoxy]-40,42-bis[(2-pyridinyl)-
methoxy]calix[6]arene (X6Me3Pic2NH2). Under an argon
atmosphere, 2-chloromethylpyridine hydrochloride (1.05 g,
6.4 mmol) and K2CO3 (2.2 g, 16 mmol) were introduced
into a solution of X6Me3H2(NHBoc) (1.86 g, 1.6 mmol) in
DMF (100 mL). The mixture was stirred for 3 h at 1508C.
The solvent was evaporated under reduced pressure. The
residue was dissolved in Et2O. The organic solution was
washed once with water, twice with brine and once with
water, dried (Na2SO4) and evaporated under reduced
pressure. The residue was dissolved in a CHCl3/CF3COOH
5:1 mixture (48 mL). The solution was stirred for 1 h and
evaporated under reduced pressure. The oily residue was
dissolved in CH2Cl2. The organic solution was washed with
1N aq. NaOH, dried (Na2SO4) and evaporated under
reduced pressure. Trituration in pentane yielded X6Me3-
Pic2NH2 as a white powder (1.31 g). Yield: 67%. Mp:
2348C. IR (KBr): n¼1593, 1481, 1435, 1393, 1362, 1291,
1
1250 cm21. H NMR (400 MHz, CDCl3): d¼0.57 (s, 9H,
tBu1), 1.02 (s, 18H, tBu1), 1.25 (s, 18H, tBu2), 1.38 (s, 9H,
tBu2), 1.47 (s, 9H, OtBu), 2.55 (s, 4H, OCH2þNCH2), 3.40
(s, 3H, OCH3), 3.45 (d, J¼14 Hz, 2H, Ar-aCHeq), 3.55 (d,
J¼14 Hz, 2H, Ar-aCHeq), 3.62 (d, J¼14 Hz, 2H,
Ar-aCHeq), 3.88 (s, 3H, OCH3), 4.22 (d, J¼14 Hz, 2H,
Ar-aCHax), 3.45 (d, J¼14 Hz, 2H, Ar-aCHeq), 4.28 (d,
J¼14 Hz, 2H, Ar-aCHax), 4.64 (d, J¼14 Hz, 2H,
Ar-aCHax), 5.53 (s, 1H, NH), 6.17 (s, 2H, ArH1), 6.93 (d,
J¼2.0 Hz, 2H, ArH1), 6.94 (d, J¼2.3 Hz, 2H, ArH2), 6.98
(d, J¼2.0 Hz, 2H, ArH1), 7.17 (d, J¼2.3 Hz, 2H, ArH2),
7.27 (s, 2H, ArH2), 7.43 (s, 2H, OH). 13C NMR (100 MHz,
CDCl3): d¼28.7 (OC(CH3)3), 29.0 (Ar-aCH2), 30.7
(Ar-aCH2), 31.2 (C(CH3)3), 31.6 (C(CH3)3), 32.0
(Ar-aCH2), 33.7 (OC(CH3)), 33.9 (C(CH3)3), 34.2
(C(CH3)3), 40.2 (NCH2), 59.8 (OCH3), 61.6 (OCH3), 73.3
(OCH2), 124.1 (CArH), 124.2 (CArH), 124.8 (CArH), 125.5
(CArH), 126.1 (CAr–CH2), 126.2 (CAr–CH2), 126.7 (CArH),
127.8 (CArH), 131.9 (CAr–CH2), 132.2 (CAr–CH2), 133.1
(CAr–CH2), 133.3 (CAr–CH2), 142.2 (CAr), 145.7 (CAr),
1
1244 cm21. H NMR (250 MHz, CDCl3): d¼0.88 (s, 27H,
tBu), 1.32 (s, 18H, tBu), 1.38 (s, 9H, tBu), 2.28 (s, 3H,
OCH3), 2.43 (s, 6H, OCH3), 2.96 (br, 2H, NCH2CH2), 3.2–
4.8 (br m, 14H, Ar-aCHeqþAr-aCHaxþOCH2CH2), 5.10 (s,
4H, OCH2Py), 6.74 (s, 4H, ArH), 6.80 (s, 2H, ArH), 7.1–7.4

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5567
(m, 7H, ArHþPyH), 7.76 (br t, 1H, PyH), 7.89 (br d, 1H,
PyH), 8.57 (d, J¼4.6 Hz, 1H, PyH). Anal. calcd for
C83H105N3O6: C 80.35, H 8.53, N 3.39; found C 80.07, H
8.79, N 3.45.
4.50 (d, J¼15.5 Hz, 4H, Ar-aCHax), 5.03 (s, 4H, OCH2Im),
6.64 (s, 4H, ArH), 6.67 (s, 2H, ArH), 6.84 (d, J¼8.8 Hz, 1H,
ArOH-o-H), 6.92 (s, 2H, ImH), 6.98 (s, 2H, 0ImH), 7.24 (s,
6H, ArH), 8.01 (d, J¼2.8 Hz, 1H, ArOH-m -H), 8.06 (dd,
3J¼8.8 Hz, 4J¼2.8 Hz, 1H, ArOH-m-H). Anal. calcd for
C88H112N6O9·H2O: C 74.65, H 8.12, N 5.94; found C 74.78,
H 7.97, N 5.76.
4.1.4. 5,11,17,23,29,35-Hexa-tert-butyl-37,39,41-tri-
methoxy-38-[2-[[(1-methyl-2-imidazolyl)methyl]amino]-
ethoxy]-40,42-bis[(1-methyl-2-imidazolyl)methoxy]-
calix[6]arene (X6Me3Imme2NHImme). Under an argon
atmosphere, X6Me3H2(NHBoc) (400 mg, 0.345 mmol) was
added to a suspension of NaH (60% in oil, 5,18 mmol) in
THF (20 mL). After 15 min on stirring, DMF (5 mL) was
added, followed 15 min later by 2-chloromethyl-1-methyl-
imidazole hydrochloride12 (346 mg, 2,07 mmol). After 5 h
on refluxing, the solvent were concentrated under reduced
pressure to a quarter of the volume and water (50 mL) was
poured into the solution. The resulting precipitate was
collected by filtration and dissolved in CH2Cl2. The organic
layer was washed with water, dried (Na2SO4) and
evaporated under reduced pressure. The residue was
dissolved in a CH2Cl2/CF3COOH 20:1 mixture (10.5 mL).
The solution was stirred for 3 h and evaporated under
reduced pressure. The oily residue was dissolved in CH2Cl2.
The organic layer was washed once with 1N NaOH and
twice with H2O, dried over (Na2SO4) and evaporated under
reduced pressure. Trituration in pentane yielded X6Me3-
Imme2NHImme as a white powder (435 mg). Yield: 91%.
Mp: 1738C (dec.). IR (KBr): n¼1505, 1488, 1470, 1462,
1420, 1399, 1365, 1290 cm21. 1H NMR (400 MHz, CDCl3):
d¼0.76 (s, 9H, tBu), 0.78 (s, 18H, tBu), 1.37 (s, 27H, tBu),
2.16 (s, 9H, OCH3), 3.08 (br t, 2H, NCH2CH2O), 3.21 (d,
J¼15 Hz, 4H, Ar-aCHeq), 3.38 (d, J¼15 Hz, 2H, Ar-
aCHeq), 3.69 (s, 3H, NCH3), 3.89 (s, 6H, NCH3), 3.99 (br t,
2H, OCH2CH2N), 4.01 (s, 2H, NCH2Im), 4.46 (d, J¼15 Hz,
4H, Ar-aCHax), 4.54 (d, J¼15 Hz, 2H, Ar-aCHax), 5.02 (s,
4H, OCH2Im), 6.60 (s, 2H, ArH), 6.64 (s, 4H, ArH), 6.82 (s,
1H, ImH), 6.92 (s, 3H, ImH), 6.98 (s, 2H, ImH), 7.23 (s, 6H,
ArH). Anal. calcd for C86H113N7O6·0.5H2O: C 76.52, H
8.51, N 7.26; found C 76.78, H 8.56, N 6.74.
4.1.6. 5,11,17,23,29,35-Hexa-tert-butyl-37,39,41-tri-
methoxy-38-[2-[[(3,5-di-tert-butyl-2-hydroxy)benzyl]-
amino]-ethoxy]-40,42-bis[(1-methyl-2-imidazolyl)-
methoxy]calix[6]arene (X6Me3Imme2NHArtBu OH). The
2
title compound was synthesized from X6Me3Imme2NH2
(890 mg, 0.71 mmol) following the procedure described for
X6Me3Imme2NHArNO2OH with EtOH (50 mL), 2-hydroxy-
3,5-di-tert-butyl-benzaldehyde (251 mg, 1.07 mmol) and
NaBH4 (54 mg, 1.42 mmol). Work-up with CH2Cl2 and
recrystallization in acetonitrile yielded X6Me3Imme2-
NHArtBu OH as a white powder (810 mg). Yield: 76%.
2
Mp: 2398C. IR (KBr): n¼1500, 1492, 1480, 1452, 1414,
1
1414, 1392, 1362, 1287, 1245 cm21. H NMR (250 MHz,
CDCl3): d¼0.76 (s, 9H, tBu), 0.79 (s, 18H, tBu), 1.27 (s, 9H,
tBu), 1.37 (s, 27H, tBu), 1.39 (s, 9H, tBu), 2.15 (s, 3H,
OCH3), 2.17 (s, 6H, OCH3), 3.10 (br t, 2H, NCH2CH2), 3.21
(d, J¼14.6 Hz, 4H, Ar-aCHeq), 3.41 (d, J¼14.7 Hz, 2H, Ar-
aCHeq), 3.89 (s, 6H, NCH3), 4.03 (br t, 2H, OCH2CH2),
4.10 (s, 2H, NCH2Im), 4.45 (d, J¼14.6 Hz, 4H, Ar-aCHax),
4.52 (d, J¼14.7 Hz, 2H, Ar-aCHax), 5.01 (s, 4H, OCH2Im),
6.61 (s, 2H, ArH), 6.65 (s, 4H, ArH), 6.89 (d, J¼2 Hz, 1H,
ArOHH), 6.91 (s, 2H, ImH), 6.97 (d, J¼1.2 Hz, 2H, ImH),
7.21 (d, J¼2 Hz, 1H, ArOHH), 7.23 (s, 2H, ArH), 7.24 (s,
4H, ArH). Anal. calcd for C96H131N5O8·H2O: C 77.74, H
8.90, N 4.72; found C 77.48, H 9.02, N 4.74.
4.1.7. 5,11,17,23,29,35-Hexa-tert-butyl-37,39,41-tri-
methoxy-38-[2-[[(5-methoxy-2-hydroxy)benzyl]amino]-
ethoxy]-40,42-bis[(1-methyl-2-imidazolyl)methoxy]-
calix[6]arene (X6Me3Imme2NHArOMeOH). The title
compound was synthesized from X6Me3Imme2NH2
(500 mg, 0.40 mmol) following the procedure described
for X6Me3Imme2NHArNO2OH with EtOH (50 mL),
2-hydroxy-5-methoxy-benzaldehyde (0.10 mL, 0.80 mmol)
and NaBH4 (45.4 mg, 1.2 mmol). Work-up with CH2Cl2
and recrystallization in CH2Cl2/pentane yielded X6Me3-
Imme2NHArOMeOH as a white powder (384 mg). Yield:
69%. Mp: 1808C. IR (KBr): n¼1500, 1492, 1480, 1452,
4.1.5. 5,11,17,23,29,35-Hexa-tert-butyl-37,39,41-tri-
methoxy-38-[2-[[(5-nitro-2-hydroxy)benzyl]amino]-
ethoxy]-40,42-bis[(1-methyl-2-imidazolyl)methoxy]-
calix[6]arene (X6Me3Imme2NHArNO2OH). 2-Hydroxy-5-
nitro-benzaldehyde (100.5 mg, 0.60 mmol) was introduced
into a solution of X6Me3Imme2NH2 (500 mg, 0.40 mmol) in
EtOH (50 mL). The yellow mixture was stirred for 1 h at
room temperature. NaBH4 (30.3 mg, 0.80 mmol) was added
at 08C. The solution was stirred for 1 h at room temperature.
1N aq. HCl was added until a white precipitate was formed.
The suspension was stirred for 5 min and 1N aq. NaOH was
added (pH <11–12). The suspension was extracted with
AcOEt. The organic layer was washed with H2O, dried
(Na2SO4) and evaporated under reduced pressure.
Recrystallization in CH2Cl2/pentane yielded X6Me3Imme2-
NHArNO2OH as a yellow powder (384 mg). Yield: 73%.
Mp: 1848C. IR (KBr): n¼1589 (NO2), 1499, 1492, 1480,
1
1414, 1392, 1362, 1287, 1245 cm21. H NMR (250 MHz,
CDCl3): d¼0.78 (s, 27H, tBu), 1.37 (s, 27H, tBu), 2.17 (s,
9H, OCH3), 3.07 (br t, 2H, NCH2CH2), 3.22 (d, J¼15.4 Hz,
4H, Ar-aCHeq), 3.40 (d, J¼14.8 Hz, 2H, Ar-aCHeq), 3.73
(s, 3H, p-OCH3-ArOH), 3.89 (s, 6H, NCH3), 4.01 (br t, 2H,
OCH2CH2), 4.11 (s, 2H, NCH2), 4.45 (d, J¼15.5 Hz, 4H,
Ar-aCHax), 4.51 (d, J¼15.5 Hz, 2H, Ar-aCHax), 5.02 (s,
4H, OCH2Im), 6.64 (s, 7H, ArHþArOHH), 6.74 (m, 2H,
ArOHH), 6.92 (s, 2H, ImH), 6.98 (s, 2H, ImH), 7.23 (s, 2H,
ArH), 7.24 (s, 4H, ArH). Anal. calcd for C89H115N5O8·H2O:
C 76.30, H 8.42, N 5.00; found C 76.59, H 8.46, N 4.84.
1450, 1414, 1392, 1362, 1285, 1235 cm21 1H NMR
.
(250 MHz, CDCl3): d¼0.79 (s, 27H, tBu), 1.36 (s, 27H,
tBu), 2.19 (s, 9H, OCH3), 3.07 (br t, 2H, NCH2CH2), 3.23
(d, J¼15.5 Hz, 4H, Ar-aCHeq), 3.40 (d, J¼15.5 Hz, 2H, Ar-
aCHeq), 3.88 (s, 6H, NCH3), 4.00 (br t, 2H, OCH2CH2),
4.23 (s, 2H, NCH2), 4.45 (d, J¼15.5 Hz, 4H, Ar-aCHax),
4.1.8. 5,11,17,23,29,35-Hexa-tert-butyl-37,39,41-tri-
methoxy-38-[2-[[(3,5-di-tert-butyl-2-hydroxy)benzyl]-
amino]-ethoxy]-40,42-bis[(2-pyridinyl)methoxy]calix[6]-
arene (X6Me3Pic2NHArtBu OH). The title compound was
2
synthesized from X6Me3Pic2NH2 (336 mg, 0.27 mmol)

´ `
O. Seneque, O. Reinaud / Tetrahedron 59 (2003) 5563–5568
5568
following the procedure described for X6Me3Pic2-
NHArNO2OH with EtOH (20 mL), 2-hydroxy-3,5-di-tert-
butyl-benzaldehyde (76 mg, 0.32 mmol) and NaBH4
(20 mg, 540 mmol). Work-up with CH2Cl2 and purification
by column chromatography on silica gel using C6H12/
OCH2Im), 6.60 (s, 2H, ArH), 6.62 (s, 4H, ArH), 6.83 (d,
J¼2.5 Hz, 1H, ArOHH), 6.91 (s, 2H, ImH), 6.97 (d,
J¼1.2 Hz, 2H, ImH), 7.17 (d, J¼2.5 Hz, 1H, ArOHH),
7.23 (s, 2H, ArH), 7.24 (s, 4H, ArH). Anal. calcd for
C99H137N5O8·H2O: C 77.96, H 9.05, N 4.59; found C 77.93,
H 9.23, N 4.52.
AcOEt 85:15 as the eluent yielded X6Me3Pic2NHArtBu OH
2
as a white powder (200 mg). Yield: 50%. Mp: 1448C. IR
(KBr): n¼1594, 1482, 1435, 1392, 1362, 1291, 1291,
1238 cm21. H NMR (250 MHz, CDCl3): d¼0.79 (s, 9H,
1
tBu), 0.83 (s, 18H, tBu), 1.25 (s, 9H, tBu), 1.37 (s, 36H,
tBu), 2.15 (s, 3H, OCH3), 2.17 (s, 6H, OCH3), 3.10 (br m,
1H, NCHH0CH2O), 3.42 (d, J¼15 Hz, 6H, Ar-aCHeq), 4.05
(br m, 2H, NCHH0CH2OþNCH2CHH0O), 4.10 (s, 2H,
NCH2ArOH), 4.22 (br m, 1H, NCH2CHH0O), 4.53 (d,
J¼15 Hz, 2H, Ar-aCHax), 4.60 (d, J¼15 Hz, 4H, Ar-
aCHax), 5.10 (s, 4H, OCH2Py), 6.67 (s, 2H, ArH), 6.72 (s,
4H, ArH), 6.88 (d, J¼2.5 Hz, 1H, ArOHH), 7.20 (d,
J¼2.5 Hz, 1H, ArOHH), 7.22–7.29 (m, 8H, ArHþPyH),
7.80 (br t, 2H, PyH), 7.92 (br d, 2H, PyH), 8.56 (d,
J¼4.6 Hz, 2H, PyH). Anal. calcd for C98H127N3O7: C 80.67,
H 8.77, N 2.88; found C 80.87, H 9.07, N 2.83.
References
´ `
1. Seneque, O.; Rondelez, Y.; Le Clainche, L.; Inisan, C.; Rager,
M-N.; Giorgi, M.; Reinaud, O.; Eur, J. Inorg. Chem. 2001,
2597.
2. Blanchard, S.; Le Clainche, L.; M-N, R.; Chansou, B.;
Tuchagues, J.-P.; Duprat, A. F.; Le Mest, Y.; Reinaud, O.
Angew. Chem. Int. Ed. 1998, 37, 2732.
3. Compared to calix[4]arenes, calix[6]arenes are much more
difficult to selectively functionalize at the small rim. This is
not only due to their higher number of phenol units but also to
their larger size conferring to their cyclic skeleton an increased
flexibility.
´ `
4. Seneque, O.; Rager, M-N.; Giorgi, M.; Reinaud, O. J. Am.
Chem. Soc. 2000, 6183.
4.1.9. 5,11,17,23,29,35-Hexa-tert-butyl-37,39,41-tri-
methoxy-38-[2-[N-[(3,5-di-tert-butyl-2-hydroxy)-
benzyl],N-propylamino]-ethoxy]-40,42-bis[(1-methyl-2-
imidazolyl)methoxy]calix[6]arene (X6Me3Imme2-
5. Krapcho, A. P.; Menta, E.; Oliva, A.; Di Domenico, R.;
Fiocchi, L. J. Med. Chem. 1998, 41, 5429.
NPrArtBu OH). Propionaldehyde (0.12 mL, 1.78 mmol)
6. Kanamathareddy, S.; Gutsche, C. D. J. Org. Chem. 1994, 59,
3871.
2
was introduced into a solution of X6Me3Imme2NHArtBu OH
2
(435 mg, 0.30 mmol) in EtOH (20 mL).After 1 h on stirring
at room temperature, NaBH3CN (37.3 mg, 0.60 mmol) was
added and the reaction mixture was stirred for an additional
hour. 10 drop of conc. HCl was added and the suspension
was stirred for 1 h. 1N aq. NaOH was added (pH <11–12).
The suspension was extracted with CH2Cl2. The organic
layer was washed with H2O, dried (Na2SO4) and evaporated
under reduced pressure. Recrystallization in acetonitrile
7. This corresponds to the quantity required to deprotonate the
two phenol units and to neutralize the 2.5 equiv. of
2-chloromethyl-1-methylimidazole hydrochloride.
8. With NaH, no alkylated product was formed, which may well
be due to degradation of 2-chloromethylpyridine.
9. It is known that complexes of some transition metal with
secondary amine-based ligands may not be stable toward O2
and may decompose into complexes where the secondary
amine function of the ligand is oxidized into an imine. To
avoid this problem, we checked that the N3ArO ligands could
be transformed into ligands with a tertiary amine arm.
10. Ito, N. E.; Phillips, S. E. V.; Stevens, C.; Ogel, Z. B.;
McPherson, M. J.; Keen, J. N.; Yadav, K. D. S.; Knowles, P. F.
Nature 1991, 350, 87.
yielded X6Me3Imme2NPrArtBu OH as a white powder
2
(450 mg). Yield: 100%. Mp: 1498C. IR (KBr): n¼1500,
1482, 1462, 1412, 1390, 1362, 1286, 1239 cm21. 1H NMR
(250 MHz, CDCl3): d¼0.76 (s, 9H, tBu), 0.77 (s, 18H, tBu),
0.92 (t, J¼7.3 Hz, 3H, NCH2CH2CH3), 1.25 (s, 9H, tBu),
1.38 (s, 36H, tBu), 1.62 (m, 2H, NCH2CH2CH3), 2.12 (s,
3H, OCH3), 2.16 (s, 6H, OCH3), 2.68 (t, J¼7.3 Hz, 3H,
NCH2CH2CH3), 3.06 (t, J¼6.5 Hz, 2H, NCH2CH2O), 3.21
(d, J¼15.0 Hz, 4H, Ar-aCHeq), 3.33 (d, J¼15.4 Hz, 2H, Ar-
aCHeq), 3.87 (s, 2H, NCH2Im), 3.89 (s, 6H, NCH3), 4.00 (t,
J¼6.5 Hz, 2H, OCH2CH2N), 4.45 (d, J¼15.0 Hz, 4H, Ar-
aCHax), 4.50 (d, J¼15.4 Hz, 2H, Ar-aCHax), 5.02 (s, 4H,
11. Janssen, R. G.; Verboom, W.; Reinhoudt, D. N.; Casnati, A.;
Freriks, M.; Pochini, A.; Uggozoli, F.; Nieto, P. M.;
Carramolino, M.; Cuevas, F.; Prado, P.; de Mendoza, J.
Synthesis 1993, 380.
12. Reese, C. B.; Pei-Zhuo, Z. J. Chem. Soc. Perkin Trans. 1 1993,
19, 2291.