Synthesis of Lower rim polyhydroxylated calix[4]arenes

Article abstract of DOI:10.1055/s-2001-18065

Several synthetic procedures were evaluated and a protective/deprotective method, which allows the introduction of two, three, and four amide-linked polyhydroxylated units (TRIS) at the lower rim of calix[4]arenes was developed. Di- and trifunctionalized derivatives are poorly soluble in water, whereas the solubility of calix[4]arene having four polyhydroxylated amide groups is good (6 × 10^-3 M at 25 °C).

Full text of DOI:10.1055/s-2001-18065

PAPER
2105
Synthesis of Lower Rim Polyhydroxylated Calix[4]arenes
Synthesis of Lower
R
im
a
Polyhydr
r
d
g
Calix[4]aren
a
e
s
rita Segura,a Francesco Sansone,b Alessandro Casnati,b Rocco Ungaro*b
a
Departamento de Quimica Organica, Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco, 28049, Madrid, Spain
b
Dipartimento di Chimica Organica e Industriale dell’Università, Parco Area delle Scienze 17/A, 43100, Parma, Italy
Fax +39(521)905472; E-mail: ungaro@unipr.it
Received 25 June 2001; revised 6 August 2001
To the best of our knowledge, water-soluble calix[4]are-
nes bearing neutral polyhydroxylated groups at the upper
rim are known,8 but no example of this type exists for the
lower rim.19 We report in this paper the results of our sys-
Abstract: Several synthetic procedures were evaluated and a pro-
tective/deprotective method, which allows the introduction of two,
three, and four amide-linked polyhydroxylated units (TRIS) at the
lower rim of calix[4]arenes was developed. Di- and trifunctional-
ized derivatives are poorly soluble in water, whereas the solubility tematic study aimed at attaching two, three, and four units
of calix[4]arene having four polyhydroxylated amide groups is
of tris(hydroxymethyl)aminomethane (TRIS) at the lower
rim of calix[4]arenes and the solubility properties of these
good (6 ¥ 10–3 M at 25 °C).
Key words: calixarenes, protecting groups, amides, supramolecu-
lar chemistry, water-soluble calix[4]arenes
compounds in protic solvents.
Using experimental conditions similar to those of a previ-
ously reported procedure,8b we first reacted the
calix[4]arene tetraester 120 with TRIS (4) in DMSO in the
presence of K2CO3 (Scheme 1, i), but did not observe any
substantial reactivity.
In several classical applications of calixarenes1 in Su-
pramolecular Chemistry, e.g. in ionophore synthesis,2
transition metal ion binding3 and catalysis,4 the lower rim
is used as the recognition core, since the binding groups
for cation complexation are introduced in this region via
ether bonds. In this case, the upper rim usually bears sub-
stituents, which confer solubility to the ligands in the de-
sired solvent. Water solubility5 is achieved by attaching
sulfonate,6 phosphonate7 or neutral hydroxylated groups.8
Calix[4]arenes, especially when blocked in the cone con-
formation, possess, however, an apolar cavity of defined
size which can take part in the recognition of neutral mol-
ecules,9 quaternary ammonium cations10 (QUATS)+ and
anions.11
Negative results were also obtained in the reaction of
TRIS (4) with the easily available calix[4]arene tetraace-
tic acid 26d as the starting material, activated as its acyl
chloride or carrying out the reaction with 1,3-dicyclohex-
ylcarbodiimide (DCC) in the presence of 1-hydroxy-1H-
benzotriazole (HOBT)21 (Scheme 1, ii and iii). The only
positive result from a direct condensation was obtained by
reacting 2 and 4, in the presence of 1,1’-carbonyldiimida-
zole (CDI) in anhydrous DMF. This procedure gave the
desired polyhydroxylated tetraamide 3 in 80% yield
(Scheme 1, iv). Since this compound is water soluble, it
was purified from imidazole by continuous liquid-liquid
extraction of the aqueous solution with dichloromethane.
The 1H NMR spectrum of the product in DMSO-d6 clearly
showed the tetrafunctionalization because of its symmet-
rical pattern, typical of cone calix[4]arenes having a C4
symmetry. The presence of a triplet (d = 4.75), a doublet
More recently, we have been interested in the synthesis of
hybrid receptors for anions,12 amino acids13,14 and carbo-
hydrates,15 which are characterized by the presence of po-
lar groups at the upper rim, in close proximity to the
calix[4]arene apolar cavity.
In order to enhance the potential of these receptors as bi- (d = 3.59) and a broad singlet (d = 7.32) corresponding to
ologically active compounds or as models for biological the OH, CH2C and NH protons, respectively, ensured that
recognition processes, we needed to render them water the condensation had occurred with the amino group. Un-
soluble by attaching suitable solubilizing groups at the fortunately, this procedure was not reproducible and, es-
lower rim, while leaving the upper rim free for the intro- pecially if the solvent contained traces of water, the
duction of polar binding groups. Water-soluble tetraamide 3 was often obtained together with a mixture of
calix[4]arenes having anionic carboxylate16 and partially condensed derivatives, which made the isolation
sulfonate17 or cationic tretralkylammonium18 groups at of the compound in pure form difficult. To overcome this
the lower rim are known. However, charged groups can problem we resorted to an indirect protection/deprotec-
affect the binding properties of the receptors and, there- tion route. Reinhoudt and co-workers8d arrived at the same
fore, it was highly desirable to introduce at the lower rim conclusion during their synthesis of neutral, water-soluble
neutral groups, which can eventually result in water-solu- calix[4]arenes having polyhydroxylated groups at the up-
ble receptors.
per rim. They used a TRIS derivative, which was protect-
ed at the hydroxyl groups with bulky tert-
butyldimethylsilyl (TBDMS) moieties, obtained by re-
duction of the corresponding nitro derivative. We encoun-
tered some difficulties in the efficient reduction of this
compound and moreover, the condensation of tetraacid 2
Synthesis 2001, No. 14, 26 10 2001. Article Identifier:
1437-210X,E;2001,0,14,2105,2112,ftx,en;T05001SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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M. Segura et al.
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Scheme 1 Reagents and conditions: i) TRIS (4), K2CO3, DMSO, 40 °C, 72–96 h; ii) 1. (COCl)2, CH2Cl2, reflux, 6 h, 2. Et3N, TRIS (4), DMF,
r.t., 12 h; iii) HOBT, DCC, TRIS (4), DMF, –5 °C to r.t., 24 h; iv) CDI, TRIS (4), DMF, r.t., 48 h, 80%; v) 1. (COCl)2, CH2Cl2, reflux, 6 h, 2.
Et3N, 7a (or 7b), CH2Cl2, r.t., 12 h, 75%; vi) HBTU, Et3N, 7a (or 7b), THF, r.t., 12 h, 50%; vii) H2 (2 bar), Pd/C, 2:1 EtOH/HOAc, r.t., 12 h,
quantitative yield; viii) Pd(OH)2, cyclohexene/EtOH (2:3), reflux, 24 h, quantitative yield
with TBDMS protected TRIS was not successful, proba- tic acid in dichloromethane. Condensation of 7a,b with
bly because of the great steric bulk of this reagent.8d For the calix[4]arene tetraacid 2, activated as its acyl chloride
these reasons we decided to use a TRIS derivative, which or with O-benzotriazol-1-yl-N,N,N’,N’-tetramethyluroni-
was O-protected with the less bulky allyl or benzyl um hexafluorophosphate (HBTU),23 which allows for
groups.
milder reaction conditions, gave the amides 8a,b in 50–
75% yields (Scheme 1, v and vi). These protected com-
pounds were easily purified by flash chromatography on
silica gel and the benzyl derivative 8a was quantitatively
transformed into the polyhydroxylated tetraamide 3, both
using catalytic hydrogenation (Pd/C and H2) in a 2:1 eth-
anol–acetic acid mixture or with palladium hydroxide and
cyclohexene in ethanol24 (Scheme 1, vii and viii). Surpris-
ingly, the allyl protected derivative 8b was quite stable in
all tested classical deallylation procedures,25 thus show-
ing, once again, that multifunctional calixarene substrates
often challenge well-established general synthetic proce-
dures.
To this end, we first protected the amino group of 4 as tert-
butyl carbamate obtaining the compound 5 in 97% yield22
(Scheme 2).
Therefore, the benzyl protection procedure was selected
as the method for the synthesis of the other calix[4]arene
derivatives 11 (Scheme 1), 16 and 23 (Scheme 3), having
four, two and three polyhydroxylated amide functions at
the lower rim, respectively.
Scheme 2 Reagents and conditions: i) (t-BuOCO)2O, MeOH–t-
BuOH (3:2), r.t., 12 h, 97%; ii) BnBr (or allyl bromide), KOH, DMF,
r.t., 2 h, 63–65%; iii) TFA, CH2Cl2, r.t., 4 h, 94–97%
All new compounds and intermediates were fully charac-
terized by NMR (1H and 13C), mass spectrometry and ele-
mental analyses.
O-Alkylation of 5 with benzyl or allyl bromide afforded
the TRIS derivatives 6a or 6b in good yields, which were
finally transformed into the O-protected amines 7a,b in
almost quantitative yields, by treatment with trifluoroace-
While compounds 11,16 and 23 are soluble only in meth-
anol–water mixtures, tetraamide 3 is soluble in water up
to 6 ¥ 10–3 M, as determined by NMR in D2O at 300 K us-
ing potassium hydrogen phthalate as internal standard.
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Synthesis of Lower Rim Polyhydroxylated Calix[4]arenes
2107
Scheme 3 Reagents and conditions: i) NaH, t-BuOCOCH2Br, DMF, r.t., 5 h, 92% for 13 and 52% for 20; ii) CF3CO2H, r.t., 3 h, quantitative
yield; iii) 1. (COCl)2, CH2Cl2, reflux, 6 h, 2. Et3N, 7a, CH2Cl2, r.t., 12 h, 77% for 15 and 54% for 22; iv) H2 (2 bar), Pd/C, EtOH–HOAc (2:1),
r.t., 12 h, quantitative yield; v) Pd(OH)2, cyclohexene–EtOH (2:3), reflux, 24 h, quantitative yield
The 1H NMR spectrum is sharp at concentrations < 2.5 ¥ 8a to 3. Only when heated at 90 °C or treated with 12 N
10–4 M, but becomes broad in the range of 2.5 ¥ 10–4 to 6 HCl, compound 3 decomposes, giving a complex mixture
¥ 10–3 M, indicating extensive aggregation under these of products.
conditions. This is also confirmed by UV/Vis experiments
In conclusion, through a systematic study of the conden-
which show a linear dependence of the absorption only at
sation reaction between activated calix[4]arene acetic ac-
concentrations < 2.5 ¥ 10–4 M.
ids and tris(hydroxymethyl)aminomethane (TRIS) units,
These data demonstrate that at least four polyhydroxylat- we have developed both a direct and an indirect protec-
ed amide units are needed to obtain water solubility in the tion/deprotection method to link up to four TRIS units to
case of de-tert-butylated calix[4]arene units 3, but that the the lower rim of calix[4]arenes. High yields in the depro-
water solubility markedly decreases with p-tert-butyl- tection step were obtained with benzyl derivatives, where-
calix[4]arenes.
as no reaction was observed for allyl derivative 8b. We
have also shown that four TRIS moieties are needed to
give a fair water solubility to calix[4]arenes without lipo-
philic substituents at the upper rim. However, we expect
that the water solubility should increase for calixarenes
bearing at the upper rim additional polar groups such as
amino acids, peptides and carbohydrates.
We also checked the stability of compound 3 in water un-
der different conditions. It has been observed, in fact, that
a-phenoxyacetamides containing hydroxy groups in the
N-alkyl residue undergo cleavage of the acetamide bonds
in water at neutral pH on heating.26 More recently,19 in
water-soluble cavitands bearing four polyhydroxylated
residues R (Figure), the end groups rearrange from an Besides water solubility the successful introduction of
amide to an ester-linked TRIS in the presence of dilute ac- polyhydroxylated functions at the lower rim of
ids, forming an ammonium salt which enhances the water calix[4]arenes is attractive, because it offers the possibili-
solubility of the receptors.
ty of anchoring calix[4]arene receptors on hydroxylated
solid surfaces (mica, glass, etc.) and studying the recogni-
tion process on monolayers.27
All solvents were dried and distilled according to standard proce-
dures. Reagents were used as purchased. All air sensitive reactions
were carried out under N2. TLC was performed on silica gel 60-
coated aluminum sheets (Macherey-Nagel) with detection by UV at
254 nm and by heating with H2SO4 (10% in MeOH). Flash chroma-
tography was carried out on silica gel 60 (ICN, 32–63 mesh). Melt-
ing points were determined on a Gallenkamp apparatus in, under
nitrogen sealed, capillaries. NMR spectra were recorded on a Bruk-
er AC300 (1H: 300 MHz; 13C: 75 MHz) and AC100 (1H: 100 MHz;
13C: 25 MHz) spectrometers using partially deuterated solvents as
Figure Rearrangement of TRIS polyhydroxylated amides to am-
monium esters
We found that tetraamide 3 is completely stable when
warmed up to 65 °C at neutral pH for several hours, and
under the acidic conditions (HOAc) used to debenzylate
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M. Segura et al.
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internal standards. Mass spectra by chemical ionization (CI) and
electrospray ionization (ESI) methods were recorded on a Finnigan
Mat SSQ 710 spectrometer. IR spectra were recorded on a Perkin-
Elmer 298 spectrometer. Elemental analyses were obtained using a
CHN 1106 Carlo Erba instrument. For reasons of clarity and in or-
der to reduce space, the name calix[4]arene was used instead of the
original IUPAC name: pentacyclo[19.3.1.13,7.19,13.115,19]octacosa-
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecane.
raphy (hexane followed by hexane–EtOAc, 95:5); yield: 14.4 g
(65%); colorless oil.
1H NMR (100 MHz, CDCl3): d = 1.40 [s, 9 H, C(CH3)3], 3.78 [s, 6
H, C(CH2O)3], 4.49 (s, 6 H, OCH2Ph), 4.92 (br s, 1 H, NH), 7.27 (br
s, 15 H, C6H5).
13C NMR (25 MHz, CDCl3):d = 28.4 [C(CH3)3], 58.7 [C(CH2O)3],
69.5 [C(CH2O)3], 73.4 (OCH2Ph), 79.0 [C(CH3)3], 127.5 (CHarom),
128.3 (CHarom), 138.4 (Carom), 154.9 (C=O).
25,26,27,28-Tetrakis(ethoxycarbonylmethoxy)calix[4]arene (1),20
(2),6d
ESI-MS: m/z = 514.1 [(M + Na)+, 100%].
25,26,27,28-tetrakis(carboxymethoxy)calix[4]arene
5,11,17,23-tetra-tert-butyl-25,26,27,28-tetrakis(carboxymethoxy)-
calix[4]arene (9),16 25,27-dihydroxy-26,28-dipropoxycalix[4]arene
(12),28 and 25,26,27-tribenzoyloxy-28-hydroxycalix[4]arene (17)29
were synthesized according to previously described procedures.
Anal. Calcd for C30H37NO5 (491.6): C, 73.24; H, 7.59; N, 2.85.
Found: C, 73.43; H, 7.49; N, 2.72.
N-(tert-Butyloxycarbonyl)tris[(allyloxy)methyl]aminomethane
(6b)
25,26,27,28-Tetrakis{[tris(hydroxymethyl)methylamino]-car-
bonylmethoxy}calix[4]arene (3)
Synthesized from 5 (10 g, 45 mmol) and allyl bromide (21.8 mL,
252 mmol), according to the procedure used for preparing 6a. Puri-
fied by flash chromatography (hexane–EtOAc, 95:5); yield: 14.98 g
(63%); colorless oil. This product showed the same spectroscopic
properties as previously reported.22
Direct Method: A solution of 26d (130 mg, 0.20 mmol), CDI (130
mg, 0.801 mmol) and 4 (96 mg, 0.792 mmol) in anhyd DMF (15
mL) was stirred at r.t. for 48 h. The solvent was removed at reduced
pressure and the residue was dissolved in H2O and purified by con-
tinuous liquid-liquid extraction with CH2Cl2 for 2 d. After concen-
tration of the aqueous layer, compound 3 (670 mg, 80%) was
obtained as a white solid; mp 120–125 °C.
Tris[(benzyloxy)methyl]aminomethane (7a); Typical
Procedure
To a solution of 6a (7.66 g, 15.6 mmol) in CH2Cl2 (60 mL), cooled
to 0 °C was added dropwise TFA (25 mL) over a period of 30 min
and the mixture was stirred at r.t., for 4 h. The mixture was concen-
trated to dryness and the residue was partitioned between EtOAc
(100 mL) and 5% aq Na2CO3 solution (100 mL). The organic layer
was washed with brine, dried (Na2SO4), and the solvent removed
under vacuum to give the product, which was not purified further;
yield: 5.93 g (97%); yellowish oil.
1H NMR (300 MHz, DMSO-d6): d = 3.18 (d, 4 H, J = 13.5 Hz, Heq
of ArCH2Ar), 3.59 (d, 24 H, J = 5.6 Hz, CH2OH), 4.50 (s, 8 H,
OCH2CO), 4.55 (d, 4 H, J = 13.5 Hz, Hax of ArCH2Ar), 4.75 (t, 12
H, J = 5.6 Hz, CH2OH), 6.53 (br s, 12 Harom), 7.32 (s, 4 H, NH).
1H NMR (300 MHz, D2O): d = 3.49 (d, 4 H, J = 14.3 Hz, Heq of
ArCH2Ar), 3.87 (s, 24 H, CH2OH), 4.58 (d, 4 H, J = 13.3 Hz, Hax of
ArCH2Ar), 4.75 (s, 8 H, OCH2CO), 6.86 (br s, 12 Harom).
1H NMR (100 MHz, CDCl3): d = 3.47 [s, 6 H, C(CH2O)3], 4.50 (s,
6 H, OCH2Ph), 7.29 (br s, 15 H, C6H5).
13C NMR (25 MHz, CDCl3): d = 56.2 [C(CH2O)3], 72.6
[C(CH2O)3], 73.4 (OCH2Ph), 127.5 (CHarom), 128.3 (CHarom), 138.5
(Carom).
13C NMR (75 MHz, CD3OD): d = 32.3 (ArCH2Ar), 62.6 (CH2OH),
63.6 [C(CH2OH)3], 74.9 (OCH2CO), 124.1 (CHarom), 129.9
(CHarom), 135.9 (Carom), 156.5 (Carom), 172.5 (C=O).
IR (KBr): 1655 (C=O), 3395 cm–1 (OH).
ESI-MS: m/z [ion, % relative intensity] = 1090.9 [(M + Na)+, 100],
969.9 {[M + Na – HNC(CH2OH)3]+, 20}, 557.1 [(M + 2 Na)2+, 55],
554.2 [(M + H + K)2+, 70].
CI-MS: m/z [ion, % relative intensity] = 392.2 [(M + H)+, 50],
270.2 [(M – CH2OBn)+, 100].
Anal. Calcd for C25H29NO3 (391.5): C, 76.70; H, 7.47; N, 3.58.
Found: C, 76.55; H, 7.41; N, 3.60.
Anal. Calcd for C52H68N4O20 (1069.1): C, 58.42; H, 6.41; N, 5.24.
Found: C, 58.25; H, 6.23; N, 5.07.
Compound 3 was also obtained in quantitative yield from 8a (800
mg, 0.37 mmol) following the General Procedures C or D (vide in-
fra).
Tris[(allyloxy)methyl]aminomethane (7b)
Synthesized from 6b (4.27 g, 12.5 mmol), according to the proce-
dure used for preparing compound 7a; yield: 2.85 g (94%); yellow-
ish oil.
1H NMR (100 MHz, CDCl3): d = 3.34 [s, 6 H, C(CH2O)3], 3.94 (dt,
6 H, J = 1.3, 5.3 Hz, OCH2CH=CH2), 5.07–5.34 (m, 6 H,
N-(tert-Butyloxycarbonyl)tris(hydroxymethyl)aminomethane
(5)
A solution of di-tert-butyl dicarbonate (23.5 g, 107.0 mmol) in t-
BuOH (100 mL) was added to a suspension of 4 (10.0 g, 82.0 mmol)
in a 1:1 mixture of MeOH–t-BuOH (150 mL) and the mixture was
stirred at r.t. for 18 h. The solvent was removed at reduced pressure
to give a residue, which was purified by precipitation with cold
EtOAc. Vacuum filtration afforded the pure compound 5 as a white
solid (17.7 g, 97%) which showed the same spectroscopic proper-
ties as those previously reported.22
OCH2CH=CH2), 5.89 (ddt,
OCH2CH=CH2).
3 H, J = 5.3, 10.1, 17.3 Hz,
13C NMR (25 MHz, CDCl3): d = 56.1 [C(CH2O)3], 71.9, 72.2
[OCH2CH=CH2, C(CH2O)3], 116.5 (OCH2CH=CH2), 134.7
(OCH2CH=CH2).
ESI-MS: m/z [ion, % relative intensity] = 264.1 [(M + Na)+, 6],
242.1 [(M + H)+, 42], 118.9 {[M + H – 3(CH2CH=CH2)]+, 100}.
Anal. Calcd for C13H23NO3 (241.3): C, 64.70; H, 9.61; N, 5.80.
Found: C, 64.85; H, 9.73; N, 5.67.
N-(tert-Butyloxycarbonyl)tris[(benzyloxy)methyl]amino-me-
thane (6a); Typical Procedure
A solution of 5 (10.0 g, 45.0 mmol) in anhyd DMF (100 mL) was
stirred at r.t., with benzyl bromide (30 mL, 252.0 mmol). Portions
of finely ground KOH (14.14 g, 252.0 mmol) were added over a pe-
riod of 15 min. The mixture was stirred at r.t. for 2 h, concentrated
to dryness and the residue partitioned between hexane (or CH2Cl2)
(200 mL) and H2O (200 mL). The organic layer was washed with
brine, dried (Na2SO4) and the solvent removed at reduced pressure
to give the crude product, which was purified by flash chromatog-
Amides 8a,10,15,22; General Procedures
Method A: A mixture of the calix[4]arene acid 2,9,14, or 21 (1
mmol) and oxalyl chloride (7.5 mL) in anhyd CH2Cl2 (60 mL) was
refluxed for 6 h. After cooling, the solution was concentrated to dry-
ness and the residue was dried under vacuum. The resulting acid
chloride was dissolved in anhyd CH2Cl2 (20 mL) and a CH2Cl2 so-
lution (25 mL) of 7a (or 7b) (1.5 equiv/COCl group) and Et3N (2
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Synthesis of Lower Rim Polyhydroxylated Calix[4]arenes
2109
equiv/COCl group) was added and the mixture was stirred at r.t.
overnight. The solution was concentrated to dryness and the crude
product 8a,10,15,or 22, respectively, was purified by flash chroma-
tography.
(OCH2CH=CH2), 122.7 (CHarom), 128.5 (CHarom), 134.5 (Carom),
135.0 (OCH2CH=CH2), 155.9 (Carom), 169.2 (C=O).
ESI-MS: m/z [ion, % relative intensity]= 1571.9 [(M + Na)+, 61],
794.5 [(M + H + K)2+, 100].
Method B: To a solution of the calix[4]arene acid 2,9,14,or 21 (1
mmol) in anhyd THF (20 mL) were added HBTU (1.5 equiv/CO2H
group), Et3N (1.5 equiv/CO2H group) and 7a (or 7b) (1.5 equiv/
CO2H group) and the mixture was stirred at r.t. overnight. The sol-
vent was removed at reduced pressure and the residue was parti-
tioned between CH2Cl2 and 5% aq HCl. The organic phase was
washed with H2O, dried (MgSO4) and concentrated to dryness giv-
ing the crude product 8a,10,15,or 22, respectively, which was puri-
fied by flash chromatography.
Anal. Calcd for C88H116N4O20 (1549.9): C, 68.20; H, 7.54; N, 3.62.
Found: C, 68.12; H, 7.38; N, 3.57.
5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetrakis{[tris(benzylo-
xymethyl)methylamino]carbonylmethoxy}calix[4]arene (10)
Prepared according to the General Procedure A, from 916 (300 mg,
0.34 mmol); flash chromatography (hexane–EtOAc, 8:2); yield:
510 mg (63%); white solid; mp 92–93 °C.
1H NMR (300 MHz, CDCl3): d = 1.06 [s, 36 H, C(CH3)3], 3.08 (d,
4 H, J = 13.1 Hz, Heq of ArCH2Ar), 3.83 [s, 24 H, C(CH2O)3], 4.37
(s, 24 H, OCH2Ph), 4.56 (d, 4 H, J = 13.1 Hz, Hax of ArCH2Ar), 4.60
(s, 8 H, OCH2CO), 6.67 (s, 8 Harom), 6.74 (br s, 4 H, NH), 7.12–7.25
(m, 60 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 31.4 [C(CH3)3], 32.2 (ArCH2Ar),
33.8 [C(CH3)3], 60.4 [C(CH2O)3], 68.8 [C(CH2O)3], 73.2
(OCH2Ph), 74.5 (OCH2CO), 125.3 (CHarom), 127.3 (CHphenyl), 127.4
(CHphenyl), 128.2 (CHphenyl), 133.2 (Carom), 138.5 (Cphenyl), 144.8 (Car-
om), 152.9 (Carom), 169.7 (C=O).
Removal of Benzyl Protecting Groups from Amides 8a,10,15,
22; General Procedures
Method C: A suspension of benzyl derivative 8a,10,15,or 22 (0.1
mmol) and 20% Pd(OH)2 (50% w/w) in a mixture of cyclohexene
(10 mL) and EtOH (15 mL) was refluxed until conversion was com-
plete (TLC monitoring: hexane–EtOAc, 1:1 and EtOAc–i-PrOH–
H2O, 5:3:2). The mixture was cooled to r.t., filtered and the clear so-
lution concentrated under vacuum to give the product 3,11,16,or 23,
respectively, which was not purified further.
ESI-MS: m/z = 2396.4 [(M + Na)+, 100%].
Method D: A solution of benzyl derivative 8a,10,15,or 22(0.1
mmol) in a 2:1 mixture of EtOH–HOAc (24 mL) containing 10%
Pd/C was stirred under H2 (pressure: 2 bar) at r.t. until conversion
was complete (see above). The catalyst was filtered off and the fil-
trate was concentrated to dryness to give the product 3,11,16,or 23,
respectively, which was not purified further.
Anal. Calcd for C152H172N4O20 (2375.1): C, 76.87; H, 7.30; N, 2.36.
Found: C, 76.79; H, 7.45; N, 2.24.
Tetrakis{[tris(hydroxymethyl)methylamino]carbonylmethoxy}
calix[4]arene (3)
Prepared according to the General Procedure C or D from 8a
(800mg, 0.37 mmol); yield: quantitative; white solid; mp 120–125
°C.
25,26,27,28-Tetrakis{[tris(benzyloxymethyl)methylamino]-
carbonylmethoxy}calix[4]arene (8a)
Prepared from 2 (100 mg, 0.15 mmol) and isolated in 75% yield
(General Procedure A) or 50% (General Procedure B) after flash
chromatography (hexane–EtOAc, 7:3); colorless oil.
The spectral data were identical with the product 3 obtained by the
direct method (see above).
1H NMR (300 MHz, CDCl3): d = 3.00 (d, 4 H, J = 14.0 Hz, Heq of
ArCH2Ar), 3.84 [s, 24 H, C(CH2O)3], 4.35 (s, 8 H, OCH2CO), 4.37
(s, 24 H, OCH2Ph), 4.39 (d, 4 H, J = 14.0 Hz, Hax of ArCH2Ar), 6.37
(br d, 8 Harom, J = 7.2 Hz), 6.48 (br t, 4 Harom, J = 7.2 Hz), 6.63 (br
s, 4 H, NH), 7.10–7.20 (m, 60 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 31.5 (ArCH2Ar), 60.5 [C(CH2O)3],
68.7 [C(CH2O)3], 73.2 (OCH2Ph), 74.6 (OCH2CO), 122.6 (CHarom),
127.3 (CHphenyl), 127.4 (CHphenyl), 128.1 (CHphenyl), 128.4 (Carom),
134.3 (CHarom), 138.4 (Cphenyl), 155.8 (Carom), 169.3 (C=O).
5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetrakis{[tris(hydroxy-
methyl)methylamino]carbonylmethoxy}calix[4]arene (11)
Prepared according to General Procedure D, from 10 (100 mg, 0.04
mmol); quantitative yield; white solid; mp 190–192 °C.
1H NMR (300 MHz, CD3OD): d = 1.18 [s, 36 H, C(CH3)3], 3.42 (d,
4 H, J = 12.2 Hz, Heq of ArCH2Ar), 3.82 (s, 24 H, CH2OH), 4.45 (d,
4 H, J = 12.2 Hz, Hax of ArCH2Ar), 4.56 (s, 8 H, OCH2CO), 7.27 (br
s, 8 Harom).
13C NMR (75 MHz, CD3OD): d = 31.3 (ArCH2Ar), 31.7 [C(CH3)3],
35.2 [C(CH3)3], 62.7 (CH2OH), 64.1 [C(CH2OH)3], 75.8
(OCH2CO), 127.3 (CHarom), 136.1 (Carom), 149.5 (Carom), 152.3 (Car-
om), 172.3 (C=O).
ESI-MS: m/z (ion, % relative intensity] = 1315.9 [(M + Na)+, 100],
1195.8 [(M + Na – HNC(CH2OH)3)+, 25], 669.3 [(M + 2 Na)2+, 50],
666.5 [(M + H + K)2+, 65].
ESI-MS: m/z [ion, % relative intensity]= 2172.9 [(M + Na)+, 100],
1094.7 [(M + H + K)2+, 44].
Anal. Calcd for C136H140N4O20 (2150.6): C, 75.96; H, 6.56; N, 2.61.
Found: C, 76.01; H, 6.74; N, 2.48.
25,26,27,28-Tetrakis{[tris(allyloxymethyl)methylamino]-
carbonylmethoxy}calix[4]arene (8b)
Anal. Calcd for C68H100N4O20 (1293.6): C, 63.14; H, 7.79; N, 4.33.
Found: C, 62.99; H, 7.62; N, 4.19.
Prepared from 2 (100 mg, 0.15 mmol) and isolated in 75% yield
(General Procedure A) or 50% yield (General Procedure B) after
flash chromatography (hexane–EtOAc, 6:4); colorless oil.
25,27-Bis(tert-butyloxycarbonylmethoxy)-26,28-dipropoxyca-
lix[4]arene (13); Typical Procedure
1H NMR (300 MHz, CDCl3): d = 3.21 (d, 4 H, J = 14.1 Hz, Heq of
ArCH2Ar), 3.78 [s, 24 H, C(CH2O)3], 3.94 (dt, 24 H, J = 1.3, 5.4 Hz,
OCH2CH=CH2), 4.44 (s, 8 H, OCH2CO), 4.53 (d, 4 H, J = 14.1 Hz,
Hax of ArCH2Ar), 5.10 (ddt, 12 H, J = 1.3, 1.6, 10.3 Hz,
OCH2CH=CH2), 5.20 (ddt, 12 H, J = 1.3, 1.6, 17.2 Hz,
OCH2CH=CH2), 5.83 (ddt, 12 H, J = 5.4, 10.3, 17.2 Hz,
OCH2CH=CH2), 6.56 (br s, 12 Harom).
A mixture of dipropoxycalix[4]arene 1228 (800 mg, 1.57 mmol),
NaH (502 mg, 12.56 mmol, 60% oil dispersion) and tert-butyl bro-
moacetate (3.48 mL, 23.55 mmol) in anhyd DMF (20 mL) was
stirred at r.t. until the conversion was complete (TLC monitoring:
hexane–EtOAc, 7:3 or 1:1). The solvent was removed at reduced
pressure and the residue was partitioned between CH2Cl2 (25 mL)
and 5% aq HCl (25 mL). The organic layer was washed with H2O,
dried (MgSO4) and evaporated to dryness. The crude product was
13C NMR (75 MHz, CDCl3): d = 31.5 (ArCH2Ar), 60.4 [C(CH2O)3],
68.2 [C(CH2O)3], 72.2 (OCH2CH=CH2), 74.7 (OCH2CO), 116.5
Synthesis 2001, No. 14, 2105–2112 ISSN 0039-7881 © Thieme Stuttgart · New York

2110
M. Segura et al.
PAPER
25,27-Bis{[tris(hydroxymethyl)methylamino]-carbonyl-
purified by precipitation with cold MeOH; yield: 1.07 g (92%);
white solid; mp 168–170 °C.
methoxy}-26,28-dipropoxycalix[4]arene (16)
Prepared from 15 (129 mg, 0.09 mmol) according to the General
Procedure C or D; quantitative yield; white solid; mp 101–103 °C.
1H NMR (300 MHz, CDCl3): d = 1.05 (t, 6 H, J = 7.2 Hz,
OCH2CH2CH3), 1.42 [s, 18 H, C(CH3)3], 1.92 (sext, 4 H, J = 7.2 Hz,
OCH2CH2CH3), 3.20 (d, 4 H, J = 13.6 Hz, Heq of ArCH2Ar), 3.81 (t,
4 H, J = 7.2 Hz, OCH2CH2CH3), 4.68 (d, 4 H, J = 13.6 Hz, Hax of
ArCH2Ar), 4.71 (s, 4 H, OCH2CO), 6.35 (t, 2 Harom, J = 7.6 Hz),
6.37 (d, 4 Harom, J = 7.6 Hz), 6.76 (t, 2 Harom, J = 7.4 Hz), 6.87 (d, 4
1H NMR (300 MHz, CD3OD): d = 0.91 (t, 6 H, J = 7.5 Hz,
OCH2CH2CH3), 1.85 (m, 4 H, OCH2CH2CH3), 3.19 (d, 4 H,
J = 13.6 Hz, Heq of ArCH2Ar), 3.81 (s, 12 H, CH2OH), 4.09 (t, 4 H,
J = 7.7 Hz, OCH2CH2CH3), 4.24 (s, 4 H, OCH2CO), 4.44 (d, 4 H,
J = 13.6 Hz, Hax of ArCH2Ar), 6.08 (d, 4 Harom, J = 7.6 Hz), 6.25 (t,
Harom, J = 7.4 Hz).
2 Harom, J = 7.5 Hz), 6.85 (t, 2 Harom, J = 7.4 Hz), 7.01 (d, 4 Harom
J = 7.4 Hz).
,
13C NMR (25 MHz, CDCl3): d = 10.7 (OCH2CH2CH3), 23.3
(OCH2CH2CH3), 28.0 [C(CH3)3], 31.5 (ArCH2Ar), 71.1
(OCH2CO), 76.9 (OCH2CH2CH3), 80.8 [C(CH3)3], 122.2, 122.3
(CHarom), 127.8, 128.9 (CHarom), 133.9, 135.8 (Carom), 155.9, 156.1
(Carom), 169.0 (C=O).
13C NMR (75 MHz, CD3OD): d = 10.9 (OCH2CH2CH3), 24.1
(OCH2CH2CH3), 32.0 (ArCH2Ar), 62.5 (CH2OH), 63.5
[C(CH2OH)3], 74.9 (OCH2CO), 77.1 (OCH2CH2CH3), 123.0, 124.1
(CHarom), 129.0, 130.2 (CHarom), 134.2, 137.9 (Carom), 155.4, 158.4
(Carom), 172.0 (C=O).
ESI-MS: m/z = 759.2 [(M + Na)+, 100%].
Anal. Calcd for C46H56O8 (736.9): C, 74.97; H, 7.66. Found: C,
75.02; H, 7.78.
ESI-MS: m/z [ion, % relative intensity] = 853.7 [(M + Na)+, 100],
733.6 {[M + Na – HNC(CH2OH)3]+, 30}.
25,27-Bis(carboxymethoxy)-26,28-dipropoxycalix[4]arene(14);
Typical Procedure
Anal. Calcd for C46H58N2O12 (831.0): C, 66.49; H, 7.14; N, 3.37.
Found: C, 66.31; H, 7.25; N, 3.28.
A mixture of di-tert-butyl ester 13 (900 mg, 1.22 mmol) and TFA
(10 mL) was stirred for 3 h at r.t. The solvent was removed at re-
duced pressure to give a residue which upon trituration with 5% aq
HCl afforded a solid that was filtered, washed with water and dried
under vacuum, to give 760 mg (quantitative yield) of pure 14; white
solid; mp 221–223 °C.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, 6 H, J = 7.5 Hz,
OCH2CH2CH3), 1.91 (sext, 4 H, J = 7.5 Hz, OCH2CH2CH3), 3.32
(d, 4 H, J = 13.4 Hz, Heq of ArCH2Ar), 3.84 (t, 4 H, J = 7.8 Hz,
OCH2CH2CH3), 4.34 (d, 4 H, J = 13.4 Hz, Hax of ArCH2Ar), 4.69
(s, 4 H, OCH2CO), 6.38 (m, 6 Harom), 7.03 (t, 2 Harom, J = 7.4 Hz),
7.18 (d, 4 Harom, J = 7.4 Hz).
1,3-alternate-25,26,27-Tribenzoyloxy-28-propoxycalix[4]arene
(18)
A mixture of tribenzoyloxy derivative 1729 (625 mg, 0.85 mmol),
NaH (67.6 mg, 1.69 mmol, 60% oil dispersion) and propyl iodide
(0.18 mL, 1.69 mmol) in anhyd DMF (10 mL) was stirred for 1 h at
r.t. and poured into cold 5% aq HCl. The yellowish solid precipitate
obtained was filtered, washed with H2O and dried under vacuum to
give 18 (605 mg, 91%) as a white solid; mp >300 °C (dec.).
1H NMR (300 MHz, CDCl3): d = 1.10 (t, 3 H, J = 7.5 Hz,
OCH2CH2CH3), 1.92 (sext, 2 H, J = 7.5 Hz, OCH2CH2CH3), 3.57
(d, 2 H, J = 14.5 Hz, Heq of ArCH2Ar), 3.60 (s, 4 H, ArCH2Ar), 3.78
(t, 2 H, J = 7.5 Hz, OCH2CH2CH3), 3.83 (d, 2 H, J = 14.5 Hz, Hax
of ArCH2Ar), 6.42 (t, 1 Harom, J = 7.4 Hz), 6.53–6.70 (m, 9 Harom),
7.21 (dd, 2 Harom, J = 1.4, 7.1 Hz), 7.34 (t, 2 Harom, J = 7.2 Hz), 7.42
(d, 2 Harom, J = 7.2 Hz), 7.55 (t, 3 Harom, J = 7.7 Hz), 7.63 (t, 2 Harom
J = 7.2 Hz), 7.75 (t, 2 Harom, J = 7.4 Hz), 7.83 (d, 4 Harom, J = 7.2
Hz).
13C NMR (25 MHz, CDCl3): d = 10.0 (OCH2CH2CH3), 22.5
(OCH2CH2CH3), 30.8 (ArCH2Ar), 71.7 (OCH2CO), 78.9
(OCH2CH2CH3), 123.4, 124.2 (CHarom), 128.2, 129.4 (CHarom),
132.6, 135.3 (Carom), 152.5, 156.1 (Carom), 171.4 (C=O).
,
ESI-MS: m/z = 645.1 [(M + Na – 2 H)–, 100%].
13C NMR (75 MHz, CDCl3): d = 10.4 (OCH2CH2CH3), 23.6
(OCH2CH2CH3), 37.2, 37.4 (ArCH2Ar), 73.0 (OCH2CH2CH3),
122.1, 124.7, 125.0, 127.6, 128.1, 128.3, 128.9, 130.4, 130.5, 130.6,
131.3, 131.5, 132.0, 133.0, 133.4, 133.6, 133.9 (Carom, CHarom),
147.9 (Carom), 157.0 (Carom), 164.4 (C=O).
Anal. Calcd for C38H40O8 (624.7): C, 73.06; H, 6.45. Found: C,
72.90; H, 6.55.
25,27-Bis{[tris(benzyloxymethyl)methylamino]-carbonyl-
methoxy}-26,28-dipropoxycalix[4]arene (15)
Prepared according to the General Procedure A, from 14 (200 mg,
0.32 mmol); flash chromatography (hexane–EtOAc, 7:3); yield:
335 mg (77%); colorless oil.
CI-MS: m/z = 778.3 [M+, 100%].
Anal. Calcd for C52H42O7 (778.9): C, 80.19; H, 5.43. Found: C,
80.27; H, 5.51.
1H NMR (300 MHz, CDCl3): d = 0.76 (t, 6 H, J = 7.4 Hz,
OCH2CH2CH3), 1.74 (m, 4 H, OCH2CH2CH3), 3.23 (d, 4 H,
J = 13.7 Hz, Heq of ArCH2Ar), 3.88 (t, 4 H, J = 7.7 Hz,
OCH2CH2CH3), 3.92 [s, 12 H, C(CH2O)3], 4.28 (s, 4 H, OCH2CO),
4.36 (d, 4 H, J = 13.7 Hz, Hax of ArCH2Ar), 4.50 (s, 12 H, OCH2Ph),
6.02 (d, 4 Harom, J = 7.5 Hz), 6.25 (t, 2 Harom, J = 7.5 Hz), 6.83 (br s,
2 H, NH), 6.93 (t, 2 Harom, J = 7.4 Hz), 7.05 (d, 4 Harom, J = 7.4 Hz),
7.24 (s, 30 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 10.2 (OCH2CH2CH3), 23.2
(OCH2CH2CH3), 31.3 (ArCH2Ar), 60.4 [C(CH2O)3], 68.4
[C(CH2O)3], 73.3 (OCH2Ph), 74.4 (OCH2CO), 75.8
(OCH2CH2CH3), 121.9, 122.8 (CHarom), 127.3 (CHphenyl), 127.4
(CHphenyl), 127.7 (CHarom), 128.2 (CHphenyl), 129.3 (CHarom), 132.0,
136.4 (Carom), 138.1 (Cphenyl), 154.7, 157.5 (Carom), 168.9 (C=O).
25,26,27-Trishydroxy-28-propoxycalix[4]arene (19)
A solution of KOH (221 mg, 3.94 mmol) in H2O (2 mL) was added
to a suspension of 18 (550 mg, 0.76 mmol) in EtOH (20 mL) and
the mixture was refluxed overnight. The solution was concentrated
to dryness and the residue was partitioned between CH2Cl2 and 5%
aq HCl. The organic phase was washed with 10% aq NaHCO3 solu-
tion and H2O, dried (MgSO4) and concentrated at reduced pressure.
The residue was purified by precipitation with cold Et2O, affording
the title compound (314 mg, 95%) as a white solid; mp 260–262 °C.
1H NMR (300 MHz, CDCl3): d = 1.28 (t, 3 H, J = 7.5 Hz,
OCH2CH2CH3), 2.19 (sext, 2 H, J = 7.2 Hz, OCH2CH2CH3), 3.45
(d, 4 H, J = 13.5 Hz, Heq of ArCH2Ar), 4.12 (t, 2 H, J = 6.9 Hz,
OCH2CH2CH3), 4.27 (d, 2 H, J = 13.7 Hz, Hax of ArCH2Ar), 4.37
(d, 2 H, J = 13.0 Hz, Hax of ArCH2Ar), 6.66 (t, 2 Harom, J = 7.5 Hz),
6.67 (t, 1 Harom, J = 7.5 Hz), 6.86 (t, 1 Harom, J = 7.5 Hz), 6.99 (d, 2
CI-MS: m/z = 1371.8 [(M + H)+, 100%].
Anal. Calcd for C88H94N2O12 (1371.7): C, 77.06; H, 6.91; N, 2.04.
Found: C, 77.18; H, 7.03; N, 1.95.
Harom, J = 7.5 Hz), 7.01 (d, 2 Harom, J = 7.5 Hz), 7.05 (d, 2 Harom
,
Synthesis 2001, No. 14, 2105–2112 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Lower Rim Polyhydroxylated Calix[4]arenes
2111
J = 7.5 Hz), 7.07 (d, 2 Harom, J = 7.5 Hz), 9.40 (s, 2 H, OH), 9.70 (s,
1 H, OH).
13C NMR (75 MHz, CDCl3): d = 10.7 (OCH2CH2CH3), 23.3
(OCH2CH2CH3), 31.5, 31.9 (ArCH2Ar), 79.0 (OCH2CH2CH3),
120.9, 121.9 (CHarom), 126.1, 128.4, 128.7, 128.8, 129.3, 134.2 (Car-
om, CHarom), 150.8 (Carom), 151.4 (Carom).
OCH2CH2CH3], 4.25 (d, 2 H, J = 14.5 Hz, Hax of ArCH2Ar), 4.37
(s, 6 H, OCH2Ph), 4.41 (m, 4 H, OCH2CO), 4.48 (s, 12 H, OCH2Ph),
4.61 (s, 2 H, OCH2CO), 6.15 (d, 2 Harom, J = 7.4 Hz), 6.20 (d, 2
Harom, J = 7.4 Hz), 6.31 (br s, 1 H, NH), 6.35 (t, 2 Harom, J = 7.5 Hz),
6.75 (br s, 2 H, NH), 6.81–6.92 (m, 6 Harom), 7.17–7.29 (m, 45 H,
C6H5).
13C NMR (75 MHz, CDCl3): d = 10.4 (OCH2CH2CH3), 23.0
(OCH2CH2CH3), 31.2, 31.6 (ArCH2Ar), 60.3, 60.4 [C(CH2O)3],
68.6, 68.8 [C(CH2O)3], 73.1, 73.2 (OCH2Ph), 73.9, 74.4
(OCH2CO), 76.2 (OCH2CH2CH3), 122.0, 122.6, 122.8 (CHarom),
127.3, 127.4 (CHphenyl), 127.9, 128.0 (CHarom), 128.2 (CHphenyl),
128.9, 129.2 (CHarom), 132.8, 133.0, 135.7, 136.0 (Carom), 138.3
(Cphenyl), 154.7, 155.3, 157.1 (Carom), 168.9, 169.0 (C=O).
CI-MS: m/z [ion, relative intensity] = 466.1 [M+, 100], 423.1 [(M –
Pr)+, 55].
Anal. Calcd for C31H30O4 (466.6): C, 79.80; H, 6.48. Found: C,
79.82; H, 6.32.
25,26,27-Tris(tert-butyloxycarbonylmethoxy)-28-propoxycalix-
[4]arene (20)
Synthesized from 19 (216 mg, 0.46 mmol) according to the proce-
dure described for 13; yield: 193 mg (52%); white solid; mp 230 °C
(dec.).
ESI-MS: m/z = 1783.4 [(M + Na)+, 100%].
Anal. Calcd for C112H117N3O16 (1761.2): C, 76.38; H, 6.70; N, 2.39.
Found: C, 76.32; H, 6.63; N, 2.29.
1H NMR (300 MHz, CDCl3): d = 1.00 (t, 3 H, J = 7.4 Hz,
OCH2CH2CH3), 1.44 [s, 18 H, C(CH3)3], 1.47 [s, 9 H, C(CH3)3],
1.91 (m, 2 H, OCH2CH2CH3), 3.18 (d, 2 H, J = 13.4 Hz, Heq of
ArCH2Ar), 3.22 (d, 2 H, J = 13.4 Hz, Heq of ArCH2Ar), 3.86 (t, 2 H,
J = 7.3 Hz, OCH2CH2CH3), 4.59 (s, 2 H, OCH2CO), 4.62 (s, 4 H,
OCH2CO), 4.69 (d, 2 H, J = 13.5 Hz, Hax of ArCH2Ar), 4.81 (d, 2
H, J = 13.5 Hz, Hax of ArCH2Ar), 6.52–6.68 (m, 12 Harom).
13C NMR (75 MHz, CDCl3): d = 10.6 (OCH2CH2CH3), 23.2
(OCH2CH2CH3), 28.1 [C(CH3)3], 31.3, 31.6 (ArCH2Ar), 71.7, 71.9
(OCH2CO), 77.2 (OCH2CH2CH3), 80.9 [C(CH3)3], 122.0, 122.4,
122.5 (CHarom), 128.1, 128.3, 128.4 (CHarom), 134.4, 134.8, 135.2
(Carom), 155.9, 156.5 (Carom), 169.1, 169.2 (C=O).
25,26,27-Tris{[tris(hydroxymethyl)methylamino]-carbonyl-
methoxy}-28-propoxycalix[4]arene (23)
Prepared according to General Procedure D, from 22 (120 mg, 0.12
mmol); quantitative yield; white solid; mp 132–134 °C.
1H NMR (300 MHz, CD3OD): d = 0.92 (t, 3 H, J = 7.3 Hz,
OCH2CH2CH3), 1.87 (m, 2 H, OCH2CH2CH3), 3.49 (d, 2 H,
J = 12.2 Hz, Heq of ArCH2Ar), 3.51 (d, 2 H, J = 12.2 Hz, Heq of
ArCH2Ar), 3.84 (s, 6 H, CH2OH), 3.91 (d, 6 H, J = 11.4 Hz,
CH2OH), 3.98 (d, 6 H, J = 11.4 Hz, CH2OH), 4.15 (m, 2 H,
OCH2CH2CH3), 4.41 (d, 2 H, J = 14.4 Hz, OCH2CO), 4.49 (d, 2 H,
J = 12.0 Hz, OCH2CO), 4.61 (s, 2 H, OCH2CO), 4.79 (d, 2 H,
J = 14.9 Hz, Hax of ArCH2Ar), 6.87–6.94 (m, 4 Harom), 7.24–7.28
(m, 8 Harom).
13C NMR (75 MHz, CD3OD): d = 9.8 (OCH2CH2CH3), 22.8
(OCH2CH2CH3), 30.7, 30.8 (ArCH2Ar), 62.6, 62.8 (CH2OH), 64.0,
64.2 [C(CH2OH)3], 75.2, 76.0 (OCH2CO), 80.1 (OCH2CH2CH3),
126.1, 126.9, 127.1 (CHarom), 130.1, 130.3, 130.5, 130.6 (CHarom),
136.7, 136.8, 137.0 (Carom), 153.2, 153.7, 154.4 (Carom), 171.5, 172.0
(C=O).
CI-MS: m/z [ion, % relative intensity] = 809.4 [(M + H)+, 15], 640.4
{M + H – 3 [(CH3)2C=CH2]+, 100}.
Anal. Calcd for C40H60O10 (809.0): C, 68.55; H, 8.63. Found: C,
68.69; H, 8.81.
25,26,27-Tris(hydroxycarbonylmethoxy)-28-propoxycalix-
[4]arene (21)
Synthesized from 20 according to the procedure described for 14;
quantitative yield; white solid; mp 162–164 °C.
1H NMR (300 MHz, DMSO-d6): d = 0.93 (t, 3 H, J = 7.4 Hz,
OCH2CH2CH3), 1.87 (sext, 2 H, J = 7.4 Hz, OCH2CH2CH3), 3.23
(d, 4 H, J = 13.0 Hz, Heq of ArCH2Ar), 3.78 (t, 2 H, J = 7.4 Hz,
OCH2CH2CH3), 4.56 (d, 2 H, J = 13.4 Hz, Hax of ArCH2Ar), 4.64
(s, 6 H, OCH2CO), 4.85 (d, 2 H, J = 13.0 Hz, Hax of ArCH2Ar),
ESI-MS: m/z [ion, % relative intensity] = 972.7 [(M + Na)+, 100],
852.7 {[M + Na – HNC(CH2OH)3]+, 25}, 497.7 [(M + 2Na)2+, 55],
494.6 [(M + H + K)2+, 70].
Anal. Calcd for C49H63N3O16 (950.1): C, 61.95; H, 6.68; N, 4.42.
Found: C, 61.87; H, 6.54; N, 4.39.
6.50–6.59 (m, 4 Harom), 6.70 (d, 4 Harom, J = 7.2 Hz), 6.88 (d, 4 Harom
J = 7.6 Hz), 10.9 (br s, 3 H, OH).
,
Acknowledgement
This work was partially supported by CNR (Programma
M.U.R.S.T. - Chimica Legge 95/95) “Agenti di contrasto, di shift e
sonde luminescenti”, M.U.R.S.T. (“Supramolecular Devices” Pro-
ject) and EU (TMR grant FMRX-CT98-0231). We thank C.I.M.
(Centro Interdipartimentale Misure) dell’Università di Parma for
the NMR and Mass facilities.
13C NMR (75 MHz, CDCl3): d = 10.3 (OCH2CH2CH3), 23.0
(OCH2CH2CH3), 30.3, 30.8, 30.9 (ArCH2Ar), 72.0, 72.2
(OCH2CO), 78.6 (OCH2CH2CH3), 123.2, 124.1, 124.2 (CHarom),
128.3, 128.6, 129.1, 129.4 (CHarom), 132.8, 133.4, 135.3, 135.9 (Car-
om), 152.5, 153.4, 156.2 (Carom), 170.5, 174.8 (C=O).
ESI-MS: m/z = 663.5 [(M + Na)+, 100%].
Anal. Calcd for C37H36O10 (640.7): C, 69.36; H, 5.66. Found: C,
69.24; H, 5.71.
References
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25,26,27-Tris{[tris(benzyloxymethyl)methylamino]-carbonyl-
methoxy}-28-propoxycalix[4]arene (22)
Prepared according to the General Procedure A, from 21 (130 mg,
0.20 mmol); flash chromatography (hexane–EtOAc, 8:2); yield:
192 mg (54%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.80 (t, 3 H, J = 7.3 Hz,
OCH2CH2CH3), 1.76 (m, 2 H, OCH2CH2CH3), 3.06 (d, 2 H,
J = 13.8 Hz, Heq of ArCH2Ar), 3.20 (d, 2 H, J = 13.8 Hz, Heq of
ArCH2Ar), 3.78 [s, 6 H, C(CH2O)3], 3.92 [br s, 14 H, C(CH2O)3,
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M. Segura et al.
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Synthesis 2001, No. 14, 2105–2112 ISSN 0039-7881 © Thieme Stuttgart · New York