Unprecedented cyclisations of calix[4]arenes with glycols under the Mitsunobu protocol. Part 1: A new perspective for the synthesis of calixcrowns

Article abstract of DOI:10.1016/S0040-4039(03)01077-3

Selective ring closures of p-tert-butylthiacalix[4]arene and p-tert-butylcalix[4]arene with oligoethylene glycols were performed under the Mitsunobu protocol using the DEAD/TPP system. The method opens a new perspective for the syntheses of 1,3-calixcrowns.

Full text of DOI:10.1016/S0040-4039(03)01077-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4681–4684
Unprecedented cyclisations of calix[4]arenes with glycols under
the Mitsunobu protocol. Part 1: A new perspective for the
synthesis of calixcrowns
a
b
a,
Viktor Csokai, Alajos Gr u¨ n and Istv a´ n Bitter *
a
Department of Organic Chemical Technology, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
b
Organic Chemical Technology Research Group of the Hungarian Academy of Sciences,
Budapest University of Technology and Economics, H-1521 Budapest, Hungary
Received 13 March 2003; revised 14 April 2003; accepted 25 April 2003
Abstract—Selective ring closures of p-tert-butylthiacalix[4]arene and p-tert-butylcalix[4]arene with oligoethylene glycols were
performed under the Mitsunobu protocol using the DEAD/TPP system. The method opens a new perspective for the syntheses
of 1,3-calixcrowns. © 2003 Elsevier Science Ltd. All rights reserved.
1
2
In the last decade a great number of supermolecules
combining the unique properties of calixarenes and
In our previous paper we demonstrated for the first
time the selective O-alkylation of p-tert-butylthia-
calix[4]arene with a series of alcohols under the Mit-
1
,2
crown ethers have been described
and applied to
These studies
3
,4
13,14
analytical and separation chemistry.
sunobu protocol
using triphenylphosphine (TPP)
have been expanded to thiacalixcrowns: a series of
distally and proximally bridged mono- and bis-crown-5
and -6 ethers have been described and their metal ion
and diethyl azodicarboxylate (DEAD) in THF or tolu-
ene. In light of our results it is surprising that this
extremely effective reaction has not been utilised fully
in calixarene chemistry, apart from two literature exam-
5–9
complexing abilities assessed. A common feature of
the synthesis of calixcrowns is the base promoted cycli-
sation of calixarenes or the thia analogues with
15,16
ples.
It is also surprising but understandable,
because of the dominance of templated cyclisations,
that the Mitsunobu cyclisation of diphenols with gly-
cols has remained unexplored (only a side reaction
between 1,1%-bi-2-naphthol and a 1,3-diol derivative
1
oligoethylene glycol ditosylates. The outcome of the
reaction (bridging pattern, regio- and stereo-control) is
strongly dependent on the cyclising agents and the
template effect of the cations of the bases used. Alkali
carbonate mediated ring closures lead to 1,3-bridged
calixcrowns in cone or 1,3-alternate conformations and
generally require 1–14 days heating of the reactants in
MeCN. 1,2-Bridging can be attained with stronger
bases (NaH, alkali alcoholates) under milder conditions
17
refers to cyclic products).
These preliminaries
prompted us to explore the possibility of intramolecular
reactions between calix[4]arenes and oligoethylene gly-
cols under standard Mitsunobu conditions. The success
of a selective 1:1 versus 2:2 coupling could not be
predicted, especially if the lack of the metal ion tem-
plate which plays an important role in the formation of
crown ethers is considered.
1
0,11
and shorter times.
These protocols work with
calix[4]arene tetrols where mono- and bis-crowns can
be selectively obtained. The cyclisation of thiacalixarene
counterparts, however, cannot be stopped effectively at
the mono-stage, only biscrowns are available by this
The reactions were performed in toluene with p-tert-
butylcalix[4]arene (CA) and p-tert-butylthiacalix[4]-
arene (TCA) using commercial di-, tri- and tetra-
ethylene glycols, aza and benzo analogues thereof,
respectively, under two different conditions: (1) with the
molar ratio of the CA or TCA: (glycol/TPP/DEAD)=
6
,9
approach.
1
: (1.5/3/3) at room temperature, (2) with the molar
ratio of the CA or TCA: (glycol/TPP/DEAD)=1: (4/7/
7) at 110°C. The outcome of the reactions is outlined in
Scheme 1.
Keywords: calix[4]crowns; cyclisation; glycols; Mitsunobu reaction.
*
Corresponding author. Tel.: 36-1-463-1379; fax: 36-1-463-3648;
e-mail: ibitter@mail.bme.hu
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01077-3

4
682
V. Csokai et al. / Tetrahedron Letters 44 (2003) 4681–4684
Scheme 1. Survey of reactions of calix[4]arenes with oligoethylene glycols under the Mitsunobu conditions.
The reactions of CA and TCA were completed within
0–30 min at room temperature affording 1,3-calix-
monocrowns CA2–5 and TCA2–6 with unexpectedly
high selectivity and in yields of 30–50% referring to the
4, the biscrown-5 TCA8 was obtained in a 50% yield.
1
With the aid of this ring closure, ditopic TCA receptors
comprising different crown rings may be accessible
which are not available otherwise.
1
mmol reaction scale. However, the yields were
increased by scaling up, e.g. in 5 mmol experiments
TCA3 and TCA4 were obtained in 60–70% yields. The
short chained diethylene glycol 1 gave different results
in respect of CA and TCA. In the former case it was
not capable of bridging the distal 1,3-OH groups yield-
ing, therefore, the proximal 1,2-calixcrown-3 derivative
CA1. The 15% larger cavity of TCA prevented 1 by
intermolecular coupling from any intramolecular ring
closure, here the formation of the dimer TCA1 was
preferred. This compound is the first representative of a
koiland-type multicavity receptor in the thiacalixarene
series where two thiacalix units are connected by glycol
chains. The highly symmetric structure of TCA1 is
None of the glycols gave biscrowns with CA even under
these vigorous conditions. The differences in the reac-
tivity of TCA and CA towards the second Mitsunobu
coupling can be rationalised in terms of the acidities of
the OH groups remaining after the first reaction. With
18
TCA these values (pKa3,4=11.6–12) reach the lower
1
4
limit where the reaction is still predicted to take place.
In the case of CA, due to the acidities being weaker by
more than one order of magnitude (estimated pK
<13), the second ring closure failed.
a3,4
18
1
9
Of the compounds prepared during this study,
monocrowns CA110, 2,
20,21
22
9
3, and TCA3 have been
1
reflected by the extremely simple H NMR spectrum
characteristic of the conic 1,3-calixcrowns. The dimer
structure was unambiguously proved by positive FAB-
described already and it has been established they exist,
just like the new thiacalix[4]monocrowns TCA2 and
4–6, in cone conformations. It is worth noting here that
the traditional base promoted syntheses of the
+
MS (m/z: 1619 [M+K] ).
calix[4]monocrown-4
CA2
and
the
thia-
During the high temperature reactions of TCA using an
calix[4]monocrown-5 TCA3 have been reported to
excess of glycols 2, 3 and the TPP/DEAD reagents,
provide comparable or lower yields in extremely long
9,19
1,3-biscrowns TCA7, TCA8 could be isolated as well as
reactions.
In addition, the other monocrowns TCA2,
the dominant monocrowns TCA2, TCA3, but only in
low yields (15%). Biscrowns cannot be prepared effec-
tively by this one-pot procedure but a higher yield was
achieved in a two-step method: when thiacalixcrown-5
TCA3 was treated with tetraethylene glycol (110°C, 12
h) using a molar ratio of TCA3/3/TPP/DEAD=1/2/4/
4–6 of the thiacalixarene series and CA4, 5 of the
calixarene series have not been available until now by
any method. Thiacalix[4]biscrown TCA8 has also been
5,6,9
synthesised earlier
and found to exist, just like the
new derivative TCA7, in the 1,3-alt conformation. Here
we should emphasise that, to our knowledge, TCA4

V. Csokai et al. / Tetrahedron Letters 44 (2003) 4681–4684
4683
and 5 are the only representatives of thiacalixarene
azacrowns.
4. Thu e´ ry, P.; Nierlich, M.; Lamare, V.; Dozol, J. F.;
Asfari, Z.; Vicens, J. J. Incl. Phenom. Macro. Chem. 2000,
36, 375–408.
Two interesting questions remain to be answered: (1)
why are these reactions which involve a double alkyla-
tion during cyclisation much faster when compared to
dialkylation with simple alcohols? (2) Why is the
formation of a crown ring preferred in most cases to
intermolecular coupling?
5. Lamare, V.; Dozol, J.-F.; Thu e´ ry, P.; Nierlich, M.;
Asfari, Z.; Vicens, J. J. Chem. Soc., Perkin Trans. 2 2001,
1920–1926.
6. Gr u¨ n, A.; Csokai, V.; Parlagh, Gy.; Bitter, I. Tetrahedron
Lett. 2002, 43, 4153–4156.
12
7. Csokai, V.; Gr u¨ n, A.; Parlagh, Gy.; Bitter, I. Tetrahedron
Lett. 2002, 43, 7627–7629.
Presently, we have no firm evidence but we assume
that, after the substitution of the first OH group by a
glycol chain, the podand-like arm of the intermediate
thereby formed, acting as a tether, keeps the second
cationic phosphonium species in a beneficial molecular
environment (together with the calixarene perhaps)
facilitating by this means a rapid intramolecular cou-
pling. Glycols with medium chain lengths (2–5) can
bridge the obviously preferred diametrical positions in
both CA and TCA. The effect of the cavity sizes
8. Narumi, F.; Masumura, N.; Morohashi, N.; Kameyama,
H.; Miyano, S. J. Chem. Soc., Perkin Trans. 1 2002,
1843–1844.
9. van Leuwen, F. W. B.; Beijleveld, H.; Kooijman, H.;
Spek, A. L.; Verboom, W.; Reinhoudt, D. N. Tetra-
hedron Lett. 2002, 43, 9675–9678.
10. Arduini, A.; Fabbi, M.; Mantovani, M.; Mirone, L.;
Pochini, A.; Secchi, A.; Ungaro, R. J. Org. Chem. 1995,
60, 1454–1457.
11. Arduini, A.; McGregor, W. M.; Paganuzzi, D.; Pochini,
A.; Secchi, A.; Ugozzoli, F.; Ungaro, R. J. Chem. Soc.,
Perkin Trans. 2 1996, 839–846.
(
TCA>CA) on the outcome of reactions is reflected
mainly in the results obtained with the shortest glycol 1
(
(
CA: 1,2-intra, TCA: 1,3-inter) and the longest glycol 6
12. Bitter, I.; Csokai, V. Tetrahedron Lett. 2003, 44, 2261–
2265.
TCA: 1,3-intra, CA: no ring closure), respectively. The
latter is supposed to be too long to cyclise with CA in
a non-templated reaction.
13. Mitsunobu, O. Synthesis 1981, 1–28.
14. Hughes, D. L. Org. React. 1992, 42, 335–656.
1
5. Dondoni, A.; Marra, A.; Scherrmann, M.-C.; Casnati,
A.; Sansone, F.; Ungaro, R. Chem. Eur. J. 1997, 3,
1774–1782.
In conclusion, the Mitsunobu cyclisation with oligo-
ethylene glycols has been demonstrated to represent
an attractive alternative for the synthesis of 1,3-
monocrown-4,-5-, and 6-ethers including monoaza-
crowns in both calix[4]arene series. The main
advantages of the method are the extremely short reac-
tion times, mild conditions and similar yields in com-
parison to the traditional base promoted ring closures.
In addition, the preparation of glycol ditosylate cyclis-
ing agents can be avoided. Notwithstanding the dis-
advantages (the commercially unavailable and danger-
ous DEAD, large amount of ballast TPPO, DEHD
formed from the reagents), the method allows access to
calixcrowns in multigram scale.
16. Wang, J.; Gutsche, C. D. Struct. Chem. 2001, 12, 267–
274.
17. Takahashi, M.; Ogasawara, K. Tetrahedron: Asymmetry
1997, 8, 3125–3130.
18. Matsumiya, H.; Terazono, Y.; Iki, N.; Miyano, S. J.
Chem. Soc., Perkin Trans. 2 2002, 1166–1172.
19. NMR spectra were recorded at 298 K in CDCl3 at
500/125 MHz on a Bruker-Avance DRX-500 instrument.
General procedure for the reactions of CA and TCA with
oligoethylene glycols: To the stirred mixture of TCA (0.72
g, 1 mmol) or CA (0.65 g, 1 mmol) TPP (0.8 g, 3mmol),
glycol (1.5 mmol) in 20 ml toluene, a 40% toluene solu-
tion of DEAD (1.3 ml, 3 mmol) was added at room
temperature and allowed to react for 0.5 h. The solvent
was then removed under reduced pressure and worked up
differently: (1) TCA derivatives were triturated with
MeOH (20 ml) and filtered to give white solids (thus
TCA1 was obtained in pure form) which were purified by
chromatography on silica (eluent: hexane–EtOAc=9:1,
TCA2–7), (2) CA1 and 2 were extracted from the residue
with hexane (3×10 ml) followed by evaporation and
subsequent trituration with MeOH (CA1) or chromato-
graphy (eluent: hexane–EtOAc=8:2). The residue con-
taining CA3–5 was directly chromatographed (eluent:
hexane–EtOAc=8:2 and 9:1, respectively).
Acknowledgements
Financial support by the Hungarian Scientific Research
Found (OTKA No. T 031864 and T 034347) are grate-
fully acknowledged. The authors express their gratitude
to Dr. Gy. Horv a´ th for FAB-MS measurements. One
of the authors (V.Cs.) thanks the J o´ zsef Varga Founda-
tion for a fellowship.
10
20,21
22
9
5
References
Compounds CA1, 2,
3, TCA3 and TCA8 were
identical in every respect with the reference samples pre-
1
. Casnati, A.; Ungaro, R.; Asfari, Z.; Vicens, J. In Calix-
arenes 2001; Asfari, M.; Boehmer, V.; Harrowfield, J.;
Vicens, J., Eds.; Kluwer Academic Press: Dordrecht, The
Netherlands, 2001; pp. 365–384.
pared by base promoted cyclisations.
Compound TCA1. Mp 340–342°C; H NMR: l 8.42 (s,
4H, OH), 7.57 (s, 8H, ArH), 6.86 (s, 8H, ArH), 5.08 (bs,
1
t
8H, OCH ), 4.19 (bs, 8H, OCH ), 1.32 (s, 36H, Bu ), 0.74
2
2
t
13
2
. Ungaro, R.; Arduini, A.; Casnati, A.; Pochini, A.; Ugoz-
zoli, F. Pure Appl. Chem. 1996, 68, 1213–1218.
. Ludwig, R. Fresenius J. Anal. Chem. 2000, 103–128.
(s, 36H, Bu ); C NMR: l 156.2, 155.6, 142.1, 134.7,
129.7, 129.1, 128.3 (Ar), 72.1, (OCH ), 34.5 (C(CH ) ),
2
3 3
3
34.3 (C(CH ) ), 31.9 (C(CH ) ), 31.1 (C(CH ) ); FAB-
3
3
3 3
3 3

4
684
V. Csokai et al. / Tetrahedron Letters 44 (2003) 4681–4684
+
+
1
MS m/z (%): 1581 [M+H] (69), 1598 [M+NH ] (49), 1619
Compound TCA6. Mp 124–128°C; H NMR: l 8.10 (s,
4
+
[
M+K] (100); anal. calcd for C H O S (1582.29): C,
2H, OH), 7.65 (s, 4H, ArH), 6.92 (s, 4H, ArH), 6.69 (m,
88
108 10 8
6
6.80; H, 6.88, found: C, 66.43; H, 6.82%.
4H, ArH), 4.78 (t, 4H, OCH
(t, 4H, J=4.60, OCH ), 1.33 (s, 18H, Bu ), 0.77 (s, 18H,
Bu ); C NMR: l 155.9, 155.8, 142.5, 136.4, 134.6, 132.7,
29.2, 122.2, 122.0, 116.1 (Ar), 73.8 (ArOCH ), 71.3,
2
), 4.26 (m, 8H, OCH ), 4.09
2
1
t
Compound TCA2. Mp 272–273°C; H NMR: l 8.51 (s,
2
t
13
2
4
4
H, OH), 7.68 (s, 4H, ArH), 7.19 (s, 4H, ArH), 4.77 (t,
1
H, J=5.6, OCH ), 4.28 (t, 4H, J=5.6, OCH ), 3.94 (bs,
2
2
2
t
t
13
70.4, 70.1 (OCH ), 34.5 (C(CH ) ), 34.3 (C(CH ) ), 31.8
H, OCH ), 1.36 (s, 18H, Bu ), 0.93 (s, 18H, Bu );
C
2 3 3 3 3
2
(
(
C(CH ) ), 31.0 (C(CH ) ); anal. calcd for C H O S
3 3 3 3 54 66 8 4
NMR: l 157.1, 156.4, 147.8, 142.4, 134.7, 134.0, 128.9,
21.8 (Ar), 74.6, 71.3, 70.5 (OCH ), 34.3 (C(CH ) ), 34.2
971.35): C, 66.77; H, 6.85, found: C, 66.22; H, 6.88%.
1
2
3 3
1
Compound TCA7. Mp 275–277°C; H NMR: l 7.74 (s,
H, ArH), 3.97 (t, 8H, J=3.35, OCH ), 3.47 (t, 8H,
(
C(CH ) ), 31.7 (C(CH ) ), 31.0 (C(CH ) ); anal. calcd
3 3 3 3 3 3
8
for C H O S (835.20): C, 66.15; H, 7.00, found: C,
6
Compound TCA3. Mp 240–243°C; H NMR: l 8.04 (s,
2
4
4
2
46
58
6 4
t
J=3.4, OCH ), 2.59 (bs, 8H, OCH ), 1.34 (s, 36H, Bu );
5.89; H, 7.04%.
2
2
1
3
1
C NMR: l 156.0, 144.8, 127.4, 127.1 (Ar), 69.9, 68.5,
7.3 (OCH ), 33.3 (C(CH ) ), 30.3 (C(CH ) ); anal. calcd
6
2
3 3
3 3
H, OH), 7.67 (s, 4H, ArH), 6.93 (s, 4H, ArH), 4.74 (t,
for C H O S (949.34): C, 65.79; H, 7.22, found: C,
52
68
8 4
H, J=4.7, OCH ), 4.15 (t, 4H, J=4.7, OCH ), 3.89 (bs,
2
2
t
65.32; H, 7.17%.
H, OCH ), 3.81 (bs, 4H, OCH ), 1.34 (s, 18H, Bu ), 0.78
2
2
t
13
Compound CA4. Mp 207–210°C (eluent: hexane–
(
1
(
s, 18H, Bu ); C NMR: l 156.0, 155.9, 147.9, 142.5,
34.7, 132.7, 129.2, 122.3 (Ar), 73.2, 71.1, 70.3, 70.0
OCH ), 34.5 (C(CH ) ), 34.3 (C(CH ) ), 31.8 (C(CH ) ),
1
EtOAc=9:1); H NMR: l 7.20 (m, 2+2H, OH, ArH),
7.13 (s, 4H, ArH), 6.95 (m, 6H, ArH), 6.62 (t, 1H,
2
3 3
3 3
3 3
J=7.5, ArH), 4.43 (d, 4H, J=12.6, ArCH ), 4.14 (bs,
+
2
3
9
6
1.1 (C(CH ) ); FAB-MS m/z (%): 901 [M+Na] (100),
3 3
4
3
1
1
7
3
H, OCH ), 3.94 (m, 8H, OCH ), 3.63 (t, 4H, OCH ),
2 2 2
+
17 [M+K] (30); anal. calcd for C H O S (879.25): C,
48
62
7
4
t
.29 (d, 4H, J=12.8, ArCH ), 1.30 (s, 18H, Bu ), 0.93 (s,
2
5.57; H, 7.11, found: C, 65.23; H, 7.01%.
t
13
8H, Bu ); C NMR: l 150.7, 149.7, 147.6, 146.9, 141.3,
32.7, 129.4, 127.9, 125.5, 125.1, 115.9, 111.6 (Ar), 76.4,
0.5, 69.6 (OCH ), 51.9 (NCH ), 34.3, 34.2 (C(CH ) ),
1
Compound TCA4. Mp 236–238°C; H NMR: l 8.14 (s,
2
4
H, OH), 7.70 (s, 4H, ArH), 7.20 (bs, 2H, ArH), 6.97 (s,
H, ArH), 6.75 (bs, 2H, ArH), 6.65 (bs, 1H, ArH), 4.73
2
2
3 3
2.1, 31.4 (C(CH ) ), 31.7 (ArCH Ar); anal. calcd for
3
3
2
(bs, 4H, OCH ), 4.09 (bs, 4H, OCH ), 3.93 (bs, 4H,
2
2
C H O N (882.23): C, 78.96, H, 8.57, found: C, 78.67,
58
75
6
t
OCH ), 3.75 (bs, 4H, OCH ), 1.37 (s, 18H, Bu ), 0.81 (s,
2
2
H, 8.65%.
Compound CA5. Mp 200–202°C; H NMR: l 7.33–7.21
m, 5H, ArH), 7.19 (s, 2H, OH), 7.13 (s, 4H, ArH), 6.75
t
13
1
1
6
8H, Bu ); C NMR: l 156.0, 155.7, 148.0, 142.5, 134.8,
32.7, 129.3, 129.2, 122.2, 115.9, 111.7 (Ar), 74.0, 70.0,
9.2 (OCH2), 51.4 (NCH2), 34.5 (C(CH3)3), 34.3
1
(
(s, 4H, ArH), 4.35 (d, 4H, J=13, ArCH ), 4.05 (bs, 4H,
2
(
C(CH ) ), 31.9 (C(CH ) ), 31.1 (C(CH ) ); anal. calcd
3 3 3 3 3 3
OCH ), 4.00 (bs, 4H, OCH ), 3.94 (t, 4H, OCH ), 3.70
2
2
2
for C H O NS (954.36): C, 67.96; H, 7.08, found: C,
54
67
6
4
(bs, 2H, OCH ), 3.29 (d, 4H, J=13, ArCH ), 2.88 (t, 4H,
2 2
t
6
7.75; H, 7.04%.
t
13
OCH ), 1.32 (s, 18H, Bu ), 0.90 (s, 18H, Bu ); C NMR:
2
1
Compound TCA5. Mp 138–142°C; H NMR: l 8.07 (s,
l 150.8, 149.8, 146.8, 141.2, 140.0, 132.5, 128.7, 128.2,
127.9, 126.8, 125.5, 125.0 (Ar), 77.1, 71.3, 70.6 (OCH2),
60.8 (NCH Ar), 55.1 (NCH ), 34.2 (C(CH ) ), 32.1, 31.3
2
3
4
2
H, OH), 7.68 (s, 4H, ArH), 7.36 (m, 2H, ArH), 7.23 (m,
H, ArH), 6.92 (s, 4H, ArH), 4.72 (t, 4H, OCH ), 4.06 (t,
2
2
2
3 3
H, OCH ), 3.83 (t, 4H, OCH ), 3.73 (s, 2H, NCH Ar),
(C(CH ) ), 31.7 (ArCH Ar); anal. calcd for C H O N
2
2
2
3 3 2 59 77 6
t
t
.92 (t, 4H, NCH ), 1.34 (s, 18H, Bu ), 0.77 (s, 18H, Bu );
(896.26): C, 79.07, H, 8.66, found: C, 79.24, H, 8.53%.
20. Yamamoto, H.; Shinkai, S. Chem. Lett. 1994, 1115–1118.
21. Asfari, Z.; Thuery, P.; Nierlich, M.; Vicens, J. Aust. J.
Chem. 1999, 52, 343–350.
2
1
3
C NMR: l 155.9, 155.7, 147.7, 142.3, 136.3, 134.6,
32.5, 129.1, 128.7, 128.1, 126.8, 122.1, 120.5, (Ar), 73.3,
9.8, 69.7 (OCH ), 61.1 (NCH Ar), 53.2 (NCH ), 34.4
1
6
2
2
2
(
(
6
C(CH ) ), 34.2 (C(CH3)3), 31.7 (C(CH3)3), 31.0
22. Ghidini, E.; Ugozzoli, F.; Ungaro, R.; Harkema, S.;
El-Fadl, A. A.; Reinhoudt, D. N. J. Am. Chem. Soc.
1990, 112, 6979–6985.
3
3
C(CH ) ); anal. calcd for C H O NS (968.39): C,
3 3 55 69 6 4
8.22; H, 7.18, found: C, 67.93; H, 7.11%.