Chemo- and stereocontrolled alkylation of 1,2-disubstituted at the lower rim 1,2-alternate p-tert-butylthiacalix[4]arene

Article abstract of DOI:10.1016/j.mencom.2011.01.017

1,2-Alternate p-tert-butylthiacalix[4]arene bearing at the lower rim 1,2-positioned acetamide fragments reacts with ethyl bromoacetate to give mono-O-alkylation product when Na₂CO₃ is used as a base and O,O′,N,N′-tetraalkylation one in the case of K ₂CO₃.

Full text of DOI:10.1016/j.mencom.2011.01.017

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 41–43
Chemo- and stereocontrolled alkylation of 1,2-disubstituted
at the lower rim 1,2-alternate p-tert-butylthiacalix[4]arene
Ivan I. Stoikov,* Alena A. Yantemirova, Roman V. Nosov, Ajdar R. Julmetov,
Vladimir V. Klochkov, Igor S. Antipin and Alexander I. Konovalov
A. M. Butlerov Chemical Institute, Kazan University, 420008 Kazan, Russian Federation.
Fax: +7 8432 315 416; e-mail: ivan.stoikov@mail.ru
DOI: 10.1016/j.mencom.2011.01.017
1,2-Alternate p-tert-butylthiacalix[4]arene bearing at the lower rim 1,2-positioned acetamide fragments reacts with ethyl bromoacetate
to give mono-O-alkylation product when Na2CO3 is used as a base and O,O',N,N'-tetraalkylation one in the case of K2CO3.
The common approach to design of synthetic receptors is modi-
fication of macrocyclic molecular platform by variation of sub-
stituents which provides optimal spatial orientation of binding
sites.1 To choose such substituents, one should consider a number
of requirements: availability of starting macrocycle, sufficient
conformation rigidity of the molecular platform providing optimal
spatial orientation of binding sites, existence of highly effective
common procedures for functionalization of the molecular plat-
form.2,3 Products of cyclocondensation of phenols and sulfur,
namely thiacalix[4]arenes, are in a good agreement with these
requirements.4,5
Carboxamide fragment, which contains two different binding
sites – proton-donor NH group and lone electron pair of carbonyl
group is very promising for this purpose. Depending on the
substitution pattern of amide group, such thiacalixarenes either
can serve as hosts for anion binding (in the case of secondary
amide group),6 or as extragents of metal cations (in the case of
tertiary amide group).7–9 Thus, interest to N-alkylation of secondary
amide fragments attached to thiacalix[4]arene platform is obvious.
In the literature, there are only several examples of partially
substituted at the lower rim thiacalix[4]arenes in 1,2-alternate
conformation.4 Therefore, studying of reactivity of 1,2-disub-
stituted 1,2-alternate p-tert-butylthiacalix[4]arene 1 bearing
N-(4-nitrophenyl)acetamide fragments10 seemed topical. Macro-
cycles modified by ester fragments are known to recognize alkali
metal cations due to their coordination with carbonyl and alkoxyl
oxygen atoms.11 Ethyl bromoacetate is a favourable reactant for
the introduction of ester group into the macrocyclic platform.12–14
In this work, macrocycle 1 was modified by its treatment with
ethyl bromoacetate in acetone using sodium and potassium car-
bonates as the bases, in analogy with the published data.15 In the
case of sodium carbonate, monosubstitution product 2 is formed
in 87% yield, with the 1,2-alternate conformation of the macro-
cycle being retained, whereas the use of potassium carbonate leads
to formation of O,O',N,N'-tetrasubstitution product 3 accom-
panied by a conformation change of thiacalix[4]arene platform
into 1,3-alternate stereoisomer (Scheme 1).
The structures of new thiacalix[4]arene derivatives 2 and 3
were established based on 1H, 13C NMR and IR spectroscopy, mass
spectrometry (EI, ESI) and elemental analysis. The 2D NOESY
1H–1H NMR spectrum of compound 2displays cross-peaks between
spatially close protons, namely, between tert-butyl and aryl protons
(H4*b/H11, H15/H4*b, H11/H4'b, H15/H4'b, H11'/H4b, H15'/H4b),
between oxymethylene protons and aromatic protons of the
macrocycle (H7a/H5', H7'a/H3, H7+a/H5*), and between hydroxyl
proton and nitrophenylamide protons (H7*/H9', H7*/H11', H7*/H15'),
which clearly testifies that macrocycle 2 has 1,2-alternate con-
formation.
NO2
NO2
NO2
19
18
14'
15'
12
11
14
15
12'
11'
10'
O
9'
4+b
HN 9'
N
4b
4
HN
O
O
O
O
O
O
7'
4a
5
O
7
7'
5+
3+
3
O
O
S
OH7*
S
O
S
OH
S
BrCH2COOEt/
Na2CO3
BrCH2COOEt/
K2CO3
S
S
S
HO
S
S
3'
S
S
S
3'
O
O
7
5'
O
5'
O
7+
3
acetone, reflux
acetone, reflux
O
5
3*
4' b
O
O
O
O
O
O
NH9
O
9+
NH
4b
4' b
N
4*b
O
15
14
11
12
10+
O
NO2
NO2
NO2
2
1
3
Scheme 1
© 2011 Mendeleev Communications. All rights reserved.
– 41 –

Mendeleev Commun., 2011, 21, 41–43
The NOESY 1H–1H spectrum of compound 3 contains cross-
upon treatment with K2CO3 can be explained either by strong
peaks between tert-butyl protons and aryl protons (H11/H4'b
,
binding or total absence of the interaction between 1,3-alternate
compound 3 and K+ ion. Tetrasubstituted at the lower rim thia-
calix[4]arenes with amide or ester groups in 1,3-alternate posi-
tions usually show binding ability toward K+ and Cs+ ions.4,15
Generally, template effect of cesium cation is used in syntheses
of thiacalix[4]arene 1,3-alternate stereoisomers, while template
effect of potassium cation is used to prepare tetrasubstituted
product in partial cone configuration.4,15 However, formation of
tetra-O-alkylated p-tert-butylthiacalix[4]arenes in 1,3-alternate
configuration regardless of the bases used is common for alkyl-
ating reagents which do not contain coordination sites capable of
binding metal ions.4
Nevertheless, we proposed here that formation of compound
3 in 1,3-alternate configuration is caused by template effect of
alkali metal cation. For verification of this hypothesis, complex-
ation ability of synthesized macrocycles 2 and 3 towards some
monocharged metal cations (Li+, Na+, K+, Cs+) was studied.
Thiacalix[4]arenes 2 and 3, containing electron-donating binding
sites of different nature (carbonyl groups of amide fragments and
ester groups), according to literature data,4,5 can be capable of
complexation with metal cations. To estimate the ability of syn-
thesized compounds to recognize alkali metal cations, picrate
extraction was investigated in mutually saturated water–dichloro-
methane system.‡ To compare extraction ability of macrocycles
2, 3, and thiacalix[4]arene 4 depriving of amide moieties,15 the
percent extraction (E%) of alkali metal cations were measured
(Figure 1).
As predicted, introduction of additional electron-donating
binding sites, such as ester group (compound 3), leads to binding
of K+ and Cs+ cations. However, thiacalix[4]arene 2 does not
extract studied alkaline metal picrates which is obviously caused by
formation of intramolecular hydrogen bonds between amide and
ester groups.
It is interesting to compare properties of tetraester 4 in
1,3-alternate configuration with those of tetrasubstituted p-tert-
butyl thiacalix[4]arene 3 in 1,3-alternate configuration.Although
the structures of substituents at the lower rim of the macrocycle of
these compounds considerably differ, their ability to bind alkali
H15/H4'b), between tert-butyl protons and oxymethylene protons
(H7'/H4b), which confirm that macrocycle 3 has 1,3-alternate
conformation.
Selective formation of 1,2-alternate mono-O-alkylation product
in the presence of Na2CO3 can be due to retaining of intramolecular
hydrogen bonds between hydroxyl and amide groups10 in the
starting compound 1 having also 1,2-alternate conformation. The
formation of O,O',N,N'-tetrasubstituted 1,3-alternate stereoisomer
†
Synthesis of compounds 2 and 3 (general procedure). 5,11,17,23-Tetra-
tert-butyl-25,26-dihydroxy-27,28-bis[N-(4-nitrophenyl)aminocarbonyl-
methoxy]thiacalix[4]arene 1 (1 g, 1.39 mmol) was suspended in 30 ml of
dry acetone containing anhydrous alkali metal carbonate (0.29 g, 2.78 mmol
Na2CO3 or 0.38 g, 2.78 mmol K2CO3). Then ethyl bromoacetate (0.4 ml,
3.72 mmol) and 40 ml of dry acetone were added. The mixture was refluxed
for 50 h (TLC monitoring). After cooling, the solid was removed by filtra-
tion, the filtrate was evaporated to dryness under reduced pressure. Ethanol
(30 ml) was added and the solid was filtered off. Crystallization of the
resulting solid from dichloromethane–ethanol gave pure samples of 2 and 3.
5,11,17,23-Tetra-tert-butyl-25-hydroxy-26-(ethoxycarbonylmethoxy)-
27,28-bis[N-(4'-nitrophenyl)aminocarbonylmethoxy]thiacalix[4]arene 2.
White powder, yield 0.93 g (87%), mp 236°C. 1H NMR (300 MHz, CDCl3)
d: 0.67 s (9H, Me3C), 0.72 (s, 9H, Me3C), 0.92 (t, 3H, OCH2Me,
3JHH 7.2 Hz), 1.29 (s, 9H, Me3C), 1.49 (s, 9H, Me3C), 3.53 (m, 2H,
3
2
OCH2Me, JHH 7.2 Hz), 4.07 (d, 1H, OCH2CONH, JHH 15.0 Hz), 4.22
(d, 1H, OCH2CONH, 2JHH 15.0 Hz); 4.73 (q,AB system, 2H, OCH2COO,
2JHH 14.7 Hz), 4.98 (d, 1H, OCH2CONH, JHH 15.0 Hz), 5.31 (d, 1H,
2
OCH2CONH, 2JHH 15.0 Hz), 6.26 (AB part of AA'BB' system, 2H, HAr'
,
3JAB + JAB' 9.1 Hz), 6.30 s (1H, NH), 7.22 (d, 1H, HAr, JHH 2.6 Hz),
5
4
4
4
7.24 (d, 1H, HAr, JHH 2.6 Hz), 7.35 (d, 1H, HAr, JHH 2.6 Hz), 7.37 (d,
1H, HAr, 4JHH 2.6 Hz), 7.39 (d, 1H, HAr, 4JHH 2.6 Hz), 7.63 (d, 1H, HAr
,
4JHH 2.6 Hz), 7.71 (A'B' part of AA'BB' system, 2H, HAr', JAB + JAB'
9.1 Hz), 7.75 (AB part of AA'BB' system, 2H, HAr'', 3JAB + 5JAB' 9.1 Hz),
7.83 (d, 1H, HAr, 4JHH 2.6 Hz), 7.89 (d, 1H, HAr, 4JHH 2.6 Hz), 8.11 (A'B'
part of AA'BB' system, 2H, HAr'', 3JAB + 5JAB' 9.1 Hz), 9.17 (s, 1H, OH),
10.52 (s, 1H, NH). 13C NMR (100 MHz, CDCl3) d: 13.85, 14.10, 30.29,
30.55, 30.62, 31.05, 31.45, 34.05, 34.25, 34.61, 60.82, 61.57, 64.63, 66.59,
68.21, 69.15, 71.21, 118.40, 119.22, 120.03, 120.20, 124.21, 124.50, 125.10,
126.52, 126.71, 127.47, 127.89, 128.03, 128.10, 128.40, 128.51, 129.10,
129.30, 129.52, 130.01, 131.17, 133.79, 134.91, 135.70, 142.23, 142.91,
143.15, 143.61, 144.20, 144.59, 147.83, 148.75, 149.11, 149.83, 150.30,
152.72, 153.61, 154.65, 156.50, 157.32, 157.51, 165.78, 166.21, 166.41,
3
5
90
80
70
60
50
40
30
20
10
0
4
3
167.82, 168.01. 1H–1H NOESY spectrum: H4b/H3, H4'b/H3', H4+b/H3+
,
OEt
t
Bu
OEt
O
H4b/H5, H4+b/H5+, H4'b/H5', H3*/H4*b, H4*b/H5*, H11/H4'b, H15/H4'b, H4*b/H11,
H15/H4*b, H11'/H4b, H15'/H4b, H11'/H12', H14'/H15', H11/H12, H14/H15, H7+a/H5*,
H7a/H5', H7'a/H3, H5+/H5, H3+/H5*, H3*/H3', H11'/H9', H15'/H9', H7*/H9',
H7*/H11', H7*/H15', H9+/H10+. IR (Nujol, n/cm–1): 3378 (NH), 3321 (OH),
1734 [C(O)OEt], 1715, 1613, 1600 [C(O)NH], 1541, 1508, 1378, 1328
(NO2), 1111, 1088 (Ar–H). MS (EI), m/z: 1162.3 (calc. for [M+], m/z:
1162.4). Found (%): C, 60.95; H, 5.48; N, 4.76. Calc. for C60H66N4O12S4
(%): C, 61.94; H, 5.72; N, 4.82.
But
S
O
S
O
S
4
O
3
S
O
O
O
But
t
O
OEt
OEt
Bu
5,11,17,23-Tetra-tert-butyl-25,26-bis(ethoxycarbonylmethoxy)-27,28-
bis[N-(ethoxycarbonylmethyl)-N-(4-nitrophenyl)aminocarbonylmethoxy]-
thiacalix[4]arene 3. White powder, yield 0.49 g (38%), mp 227°C. 1H NMR
(300 MHz, CDCl3) d: 1.18 (s, 18H, Me3C), 1.20 (s, 18H, Me3C), 1.26 (t,
12H, OCH2Me, 3JHH 7.2 Hz), 4.18 (m, 8H, OCH2Me, 3JHH 7.2 Hz), 4.41
(ABquadruplet,4H,OCH2CON,2JHH 17.7Hz),4.55(s,4H,OCH2COOEt),
3
4
2
2
4
2
2
3
4
Li+
Na+
K+
Cs+
Figure 1 The percent extraction (E%) of alkali metal cations by thia-
calix[4]arenes 2–4. Extraction conditions: [L] = 2.5´10–3 mol dm–3, [MPic] =
2
4.60 (AB quadruplet, 4H, OCH2COO, JHH 13.4 Hz), 7.33 (AB part of
= 2.32´10–4 mol dm–3
.
AA'BB' system, 4H, HAr', 3JAB + 5JAB' 8.8 Hz), 7.38 (s, 4H, HAr), 7.39 (d,
4
4
‡
2H, HAr, JHH 2.6 Hz), 7.42 (d, 2H, HAr, JHH 2.6 Hz), 8.13 (A'B' part
of AA'BB' system, 4H, HAr', 3JAB + 5JAB' 8.8 Hz). 13C NMR (100 MHz,
CDCl3) d: 14.18, 14.29, 31.03, 31.09, 34.15, 34.19, 51.11, 60.55, 61.59,
67.58, 68.02, 125.05, 127.20, 127.30, 127.40, 127.61, 128.71, 133.35,
133.55, 133.69, 146.29, 146.37, 146.59, 147.41, 156.91, 157.14, 157.25,
General method for picrate extraction. Solutions of metal picrates were
prepared from aqueous picric acid solution and aqueous solution of metal
hydroxide (LiOH, NaOH, KOH, CsOH) by pH-metric titration method;
final concentration of alkali metals was 0.1 mol dm–3. Aqueous picrate
solution (3 ml, 2.32´10–4 mol dm–3) and dichloromethane solution of ligand
(L) 2–4 (3 ml, 2.5´10–3 mol dm–3) were stirred together for 0.5 h and then
kept for 1 h for phase separation at 25°C. Absorbance of the aqueous phase
prior to (A0) and after extraction (Ai) was measured at 355 nm. The per-
centage of cation extracted (%E) was calculated as ratio 100(A0 – Ai)/A0.
The values presented in Figure 1 resulted from three parallel runs, estimated
standard deviation was less than 3%.
167.06, 167.71, 168.69. 1H–1H NOESY spectrum: H11/H4'b, H15/H4'b
,
H7'/H4b, H4b/H3, H4b/H5, H4'b/H3', H4'b/H5', H9'/H10', H18/H19. IR (Nujol,
n/cm–1): 1735 [C(O)OEt], 1649 [C(O)N], 1509, 1377, 1344 (NO2), 1112,
1074 (Ar–H). MS (ESI), m/z: 1438.7 (calc. for [M + NH4+], 1438.5).
Found (%): C, 61.40; H, 4.98; N, 3.95. Calc. for C72H84N4O18S4 (%):
C, 60.83; H, 5.96; N, 3.94.
– 42 –

Mendeleev Commun., 2011, 21, 41–43
4 N. Morohashi, F. Narumi, N. Iki, T. Hattori and S. Miyano, Chem. Rev.,
metal cations does not change, except for Cs+ cation (Figure 1).
The replacement of two ester groups on the different sides of the
macrocycle in thiacalix[4]arene 4 with two bulky tertiary amide
groups lowers its binding ability towards cesium cation, and leads
to increase in selectivity of potassium ion extraction by the macro-
cycle 3. The obtained results indirectly confirm that formation of
the product 3 in 1,3-alternate configuration is caused by template
effect of potassium cation.
Thus, a new example of template effect of a cation on chemo-
and stereoselectivity of alkylation of thiacalix[4]arene derivatives
was discovered manifesting the change from 1,2-alternate con-
formation to 1,3-alternate.
2006, 106, 5291.
5 P. Lhotak, Eur. J. Org. Chem., 2004, 8, 1675.
6 I. I. Stoikov, V. A. Smolentsev, I. S. Antipin, W. Habicher, M. Gruner
and A. I. Konovalov, Mendeleev Commun., 2006, 294.
7 I. I. Stoikov, E. A. Yushkova, A. Yu. Zhukov, I. Zharov, I. S. Antipin and
A. I. Konovalov, Tetrahedron, 2008, 64, 7489.
8 I. I. Stoikov, E. A. Yushkova, A. Yu. Zhukov, I. Zharov, I. S. Antipin and
A. I. Konovalov, Tetrahedron, 2008, 64, 7112.
9 E. A. Yushkova and I. I. Stoikov, Langmuir, 2009, 25, 4919.
10 I. I. Stoikov, D. S. Ibragimova, N. V. Shestakova, D. B. Krivolapov, I. A.
Litvinov, I. S. Antipin, A. I. Konovalov and I. Zharov, Supramol. Chem.,
2009, 21, 564.
11 Z. Asfari, V. Bohmer, J. Harrowfield, J. Vicens and M. Saadioui, Calix-
arenes 2001, Kluwer Academic Publishers, Dordrecht, Boston, London,
2001.
12 N. Iki, N. Morohashi, F. Narumi, T. Fujimoto, T. Suzuki and S. Miyano,
Tetrahedron Lett., 1999, 40, 7337.
13 R. Lamartine, C. Bavoux, F.Vocanson,A. Martin, G. Senlis and M. Perrin,
This work was supported by the Federal Programme 'Research
and scientific-pedagogical cadres of innovative Russia' for 2009–
2013 (no. P1295, 09.06.2010), the Russian Foundation for Basic
Research (grant no. 09-03-00426-a) and programme of the President
of the Russian Federation grants for the state support of young
Russian scientists – doctors of sciences (no. MD-2747.2010.3).
Tetrahedron Lett., 2001, 42, 1021.
14 P. Lhotak,V. Stastny, P. Zlatuskova , I. Stibor,V. Michlova, M. Tkadlecova,
J. Havlicek and J. Sykora, Collect. Czech. Chem. Commun., 2000, 65,
757.
15 N. Iki, F. Narumi, T. Fujimoto, N, Morohashi and S. Miyano, J. Chem.
Soc., Perkin Trans. 2, 1998, 2745.
References
1 J.-M. Lehn, Proc. Natl. Acad. Sci. USA, 2002, 99, 4763.
2 J.-M. Lehn, Angew. Chem., Int. Ed. Engl., 1988, 27, 89.
3 D. J. Cram, Nobel Lectures in Chemistry 1981–1990, World Scientific
Publishing Co., Malstrom–Singapure, 1993, p. 720.
Received: 14th July 2010; Com. 10/3578
– 43 –