A novel method for the upper rim alkoxy-substitution of calix[4]arene via a bis(spirodienone) route

Article abstract of DOI:10.1016/j.tetlet.2008.11.118

A mild and efficient one-step procedure for the upper rim modification of calix[4]arene via a bis(spirodienone) is described. The bis(spirodienone) on reaction with alcohols in the presence of p-TSA affords mono- and 1,3-disubstituted alkoxy derivatives i

Full text of DOI:10.1016/j.tetlet.2008.11.118

Tetrahedron Letters 50 (2009) 770–772
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A novel method for the upper rim alkoxy-substitution of calix[4]arene via
a bis(spirodienone) route
*
Sreeja Thulasi, Ganga V. Bhagavathy, Jijy Eliyan, Luxmi R. Varma
Organic Chemistry Section, Chemical Sciences and Technology Division, National Institute for Interdisciplinary Science and Technology (CSIR), Trivandrum 695 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient one-step procedure for the upper rim modification of calix[4]arene via a bis(spirodie-
none) is described. The bis(spirodienone) on reaction with alcohols in the presence of p-TSA affords
mono- and 1,3-disubstituted alkoxy derivatives in moderate to good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 21 September 2008
Revised 19 November 2008
Accepted 28 November 2008
Available online 3 December 2008
Keywords:
p-tert-Butyl-calix[4]arene
Calix[4]bis(spirodienones)
Upper rim
Selective functionalization
Nucleophilic attack
Calix[4]bis(spirodienones) are versatile molecular skeletons
derived from p-tert-butyl-calix[4]arene.1 The rather fortuitous
discovery of bis(spirodienones) comprising three isomers (either
stereo or positional), dates back to 1992 and resulted from a mild
oxidative cyclization reaction2 of p-tert-butyl-calix[4]arene. De-
spite having a macrocyclic 14-membered cavity bordered with
two sets of carbonyl and ether linkages in a non-alternate/alter-
nate fashion, bis(spirodienones) are not suitable candidates as
ionophores. This may be attributed to the orientation of the
two carbonyl groups and ether linkages in opposite directions
thereby creating a non-congenial environment for co-ordination
of metal ions. However, bis(spirodienones) have been utilized
successfully by Biali et al. for effecting transformations of p-tert-
butyl-calix[4]arene into various analogues which are otherwise
difficult to synthesize. Derivatization of the bridging methylene
groups,3 selective aminodehydroxylation4 and replacement of
the lower rim hydroxyls with methyl groups5 are some of the
functionalizations that have been reported on bis(spirodienones).
There have also been reports on synthesis of extraannular-substi-
tuted calix[4]arenes possessing one or two fluorosubstituted
dehydroxylated rings by reaction of bis(spirodienol) with DAST
(Et2NSF3).6
lowed by selective removal of the tert-butyl groups positioned at
the upper rim. Reactions reported under this category are haloge-
nation,7 nitration,8 sulfonation,9 chloromethylation,10 acylation,11
formylation,12 etc. Both exhaustive and selective ipso-substitutions
such as sulfonation,13 chlorosulfonation,14 nitration15 and formyla-
tion16 of calixarenes requiring prior protection of the narrow rim
hydroxyls have also been reported. A few scattered reports17 have
appeared on the indirect upper rim alkoxy-substitution of
calix[n]arenes which involved multi-step conversions. Thus, the
development of a simple and more versatile approach for the direct
and selective upper rim alkoxylation of calixarene would be very
useful for the synthesis of complex molecular receptors. In this
context, the new methodology to selectively functionalize the
upper rim of the calix moiety described in this Letter assumes
importance. The acid-mediated reaction of bis(spirodienones), in
the presence of primary alcohols affords, in single step, upper
rim substituted mono- and 1,3-dialkoxy-calix[4]arenes in the cone
conformation which are stabilized by a circular array of hydrogen
bonds at the lower rim.
We came across this unprecedented reaction during our studies
on the reactivity of the dienone carbonyls towards acetal forma-
tion. When we reacted the most stable bis(spirodienone) isomer
1 with 1,2-ethylene glycol in the presence of p-TSA, in addition
to the expected cyclic acetal, a calix[4]arene with alkoxy-substitu-
tion at the upper rim was also obtained. Subsequently, we reacted
1 with dry methanol in anhydrous toluene under reflux in the pres-
ence of p-TSA (0.6 equiv) for 6 h (Scheme 1).18 The reaction mix-
ture after work up followed by column chromatography afforded
a mixture of four products 3–6.
Selective introduction of functional groups at the upper rim of
calix[n]arenes is synthetically more challenging due to the involve-
ment of two or more preliminary steps prior to functionalization.
These involve selective protection of the phenolic hydroxyls fol-
* Corresponding author. Tel.: +91 4712515275; fax: +91 4712491712.
E-mail address: lux_varma@rediffmail.com (L.RR. Varma).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.118

S. Thulasi et al. / Tetrahedron Letters 50 (2009) 770–772
771
t
be explained by the oxidative removal of a molecule of formalde-
hyde at reflux temperature of toluene as indicated in Scheme 2.
Next, we investigated the effects of various Lewis acids on this
reaction and the results are shown in Table 1.
A superior result was obtained employing BF3ÁOEt2 (entry 3) but
at the reflux temperature of toluene, mild etching of glassware was
observed due to release of hydrogen fluoride vapours. The use of
5 equiv of p-TSA gave both mono- and dimethoxy calixarenes in
OMe
t
Bu
Bu
t
Bu
O
O
OH
OH
OH
OH
HO
i
t
t
t
t
O
+
HO
OH
OH
Bu
Bu
Bu
+
Bu
O
t
t
Bu
Bu
(10%)
3
4a(51%)
1
t
t
Bu
Bu
OTs
OH
OMe
Table 1
OH
OH
OH
t
t
t
t
Reaction of calix[4]bis(spirodienone) 1 and methanol using different catalysts
HO
OH
OH
Bu
HO
Bu
+
Bu
Bu
OMe
OMe
But
But
t
Bu
OMe
O
O
5a(5%)
OH
6 (10%)
OH
OH
But
But
But
+
O
But
3
OH
+
HO
OH
i = MeOH (2a), 0.6 equiv. p-TSA, toluene, 110 ˚C, 6 h
HO
HO
O
But
Scheme 1. p-TSA-mediated reaction of calix[4]bis(spirodienone) 1 with methanol.
But
1
4a
But
5a
OMe
The 1H NMR spectrum of 3 revealed it to be p-tert-butyl-ca-
lix[4]arene. In the 1H NMR spectrum of 4a, the OH protons reso-
nated at d 10.20 and the OCH3 protons occurred at 3.64 ppm as a
sharp singlet. The tert-butyl groups appeared as two singlets at d
1.22 and d 1.19 in a 2:1 ratio. In the 13C NMR spectrum, a peak
at d 55.3 corresponding to methoxy carbon was observed. The cone
conformation was confirmed by the 13C NMR spectrum which
showed the methylene bridge carbons at d 31.6 and d 29.8.19 The
structures of the other products 5a and 6 were established on
the basis of spectral analyses (see Supplementary data).
The mechanism outlined in Scheme 2 is suggested to rationalize
the formation of products 4a and 5a. Protonation of the spiro oxy-
gen followed by the nucleophilic attack of methanol at one of the
carbon atoms bearing a tert-butyl group results in the cleavage of
the spiro bond and formation of a protonated cross-dienone. The
aromaticity of cross-dienone can be achieved by the removal of
the tert-butyl group resulting in the formation of the disubstituted
product 5a. The formation of the monosubstituted product 4a can
Entry
Lewis acida
Yield (%)
3
4a
5a
6
1
2
3
4
5
6
7
8
9
p-TSA (0.6 equiv)
p-TSA (5 equiv)
BF3ÁOEt2
16
11
6
51
32
56
5
45
22
10
13
—
Anhydrous ZnCl2
Montmorillonite K-10
Sc(OTf)3
No reaction
No reaction
17
58
8
50
2
54
—
—
11
—
—
—
—
—
Cu(OTf)2
AgOTf
Sn(OTf)2
La(OTf)3
Yb(OTf)3
Camphor sulfonic acid
26
(50:50)b
10
11
12
No reaction
No reaction
No reaction
Reaction conditions: MeOH, toluene, 110 °C, 6 h.
a
Unless otherwise stated, 0.6 equiv of Lewis acid was used.
Obtained as an inseparable mixture of 4a and 1.
b
Table 2
Reaction of calix[4]bis(spirodienone) 1 with various alcohols
But
OR
But
OR
OH
But
But
But
O
OH
But
But
O
MeOH
But
3
But
6
OH
HO
OH
2
OH
HO
O
2
O
O
2
H
O
H
O
H+
OH
OR
But
O
But
But
O
O
But
But
But
1
5a-h
4a-h
Entry
Lewis acid
Yield (%)
But
OH
But
OH
3
4
5
6
1
2
3
4
5
6
7
8
CH3OH (2a)
11
4a/32
4b/49
4c/37
4d/35
4e/30
4f/33
4g/28
5a/45
—
15
2
2
MeO
But
(2b)
17
20
22
18
12
16
20
20
26
28
31
17
18
34
OH
MeO
OH
OH
—
OH (2c)
5a
(2d)
—
OH
Formation of 4a
But
OH
But
OH
OH
(2e)
(2f)
(2g)
(2h)
—
OH
OH
5f/38
—
But
O
OH
But
OH
-CH2O
OH
4h/22
—
H CH2
4a
Reaction conditions: 2, 5 equiv p-TSA, toluene, 110 °C, 6 h.
For entries 6–8, the reaction time is 10 min.
Scheme 2. A general mechanism for the reaction of 1 in the presence of MeOH and
p-TSA.

772
S. Thulasi et al. / Tetrahedron Letters 50 (2009) 770–772
4. (a) Aleksiuk, O.; Grynszpan, F.; Biali, S. E. J. Org. Chem. 1993, 58, 1994; (b)
OMe
OH
HO
OH
OH
Aleksiuk, O.; Cohen, S.; Biali, S. E. J. Am. Chem. Soc. 1995, 117, 9645.
5. Van Gelder, J. M.; Brenn, J.; Thondorf, I.; Biali, S. E. J. Org. Chem. 1997, 62, 3511.
6. (a) Agbaria, K.; Wohnert, J.; Biali, S. E. J. Org. Chem. 2001, 66, 7059; For a review
on spirodienone calixarene derivatives, see: (b) Biali, S. E. Synlett 2003, 1.
7. Arduini, A.; Pochini, A.; Sicuri, A. R.; Secchi, A.; Ungaro, R. Gazz. Chim. Ital. 1994,
124, 129.
BBr3, DCM
0 ˚C - rt, 2 h
OH
OH
HO
OH
But
But
But
But
OH
8. (a) Verboom, W.; Durie, A.; Egberink, R. J. M.; Asfari, Z.; Reinhoudt, D. N. J. Org.
Chem. 1992, 57, 1313; (b) Kelderman, E.; Derhaeg, L.; Heesnik, G. J. T.; Verboom,
W.; Engbersen, J. F. J.; van Hulst, N. F.; Persoons, A.; Reinhoudt, D. N. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1057.
But
4a
But
7 (75%)
9. Casnati, A.; Ting, Y.; Berti, D.; Fabbi, M.; Pochini, A.; Ungaro, R.; Sciotto, D.;
Lombardo, G. G. Tetrahedron 1993, 49, 9815.
Scheme 3. Reaction of 4a with BBr3.
10. Almi, M.; Arduini, A.; Casnati, A.; Pochini, A.; Ungaro, R. Tetrahedron 1989, 45,
2177.
11. (a) Shinkai, S.; Nagasaki, T.; Iwamoto, K.; Ikeda, A.; Matsuda, T.; Iwamoto, M.
Bull. Chem. Soc. Jpn. 1991, 64, 381; (b) Conner, M.; Janout, V.; Regen, S. L. J. Org.
Chem. 1992, 57, 3744.
32% and 45% yields, respectively. Considering the cost effectiveness
and ease of handling of the various catalysts used, 5 equiv of p-TSA
in toluene was selected as the optimal acid concentration for upper
rim modifications.
12. Arduini, A.; Manfredi, G.; Pochini, A.; Sicuri, A. R.; Ungaro, R. J. Chem. Soc., Chem.
Commun. 1991, 936.
13. Atwood, J. L.; Bott, S. G. Water Soluble Calixarene Salts. A Class of Compounds with
Solid State Structures Resembling Those of Clays, in Ref. 2, p 199.
14. Coquiere, D.; Cadeau, H.; Rondelez, Y.; Giorgi, M.; Reinaud, O. J. Org. Chem.
2006, 71, 4059.
15. Redon, S.; Li, Y.; Reinaud, O. J. Org. Chem. 2003, 68, 7004.
16. Arora, V.; Chawla, H. M.; Santra, A. Tetrahedron 2002, 58, 5591.
17. (a) Morita, Y.; Agawa, T. J. Org. Chem. 1992, 57, 3659; (b) Mascal, M.; Naven, R.
T.; Warmuth, R. Tetrahedron Lett. 1995, 36, 9361; (c) Arduini, A.; Mirone, L.;
Peganuzzi, D.; Pinalli, A.; Pochini, A.; Secchi, A.; Ungaro, R. Tetrahedron 1996,
52, 6011.
With the optimal conditions in hand, we next examined the
reactivities of a variety of primary alcohols towards bis(spirodie-
nones). The reaction was found to be general with both saturated
and unsaturated alcohols yielding monosubstituted products 4
and 6 in all the cases investigated except for entries 1 and 6. Unsat-
urated alcohols (entries 6–8) were found to react faster and the
reactions were complete within 10 min (Table 2).
The reaction of 4a with BBr3 in dichloromethane at 0 °C afforded
5-hydroxycalix[4]arene 7 in 75% yield (Scheme 3).20 Although
there has been a report on the synthesis of detertiarybutylated 5-
hydroxy calix[4]arene,21 to the best of our knowledge, this is the
first synthesis of 7,11,23-tri-p-tert-butylcalix[4]arene with a hy-
droxyl group on the upper rim.
In conclusion, a direct and efficient acid-mediated protocol for
the upper rim ipso-alkoxy substitution of calix[4]arene via bis(spi-
rodienone) 1 has been described in this letter. The transformation
is distinguished by mild reaction conditions, experimental simplic-
ity and considerable generality. Studies to transform the upper
rim-substituted products to highly functionalized macrocycles
are underway and a detailed study of the reactivity of bis(spirodie-
nones) with nucleophiles such as amines and thiols is in progress.
18. Typical experimental procedure:
A mixture of bis(spirodienone) 1 (50 mg,
0.08 mmol), methanol (4 equiv) and p-TSA (60 mol %) in toluene was stirred
at reflux (110 °C). Refluxing was continued until the reaction was complete
as shown by TLC (ꢀ12 h). The solvent was removed under reduced pressure.
The reaction mixture was worked-up using dichloromethane–water mixture
and the solid mass obtained was purified by column chromatography. With
unsaturated alcohols, the reaction was complete within 10 min as indicated
by thin layer chromatography. Spectral characterization of products 4a:
Yield: 32% as a white solid. Rf: 0.90, mp: Decomposed >240 °C. IR (KBr) mmax
:
d
3173, 2960, 2858, 1800, 1259, 1053 cmÀ1 1H NMR (300 MHz, CDCl3):
.
10.20 (s, OH, 4H), 7.02 (m, ArH, 6H), 6.55 (s, ArH, 2H), 4.24 (d, J = 12.0 Hz,
ArCH2Ar, 4H), 3.64 (s, OMe, 3H), 3.46 (br s, ArCH2Ar, 4H), 1.22 (s, t-Bu, 18H),
1.19 (s, t-Bu, 9H). 13C NMR (75 MHz, CDCl3): d 153.9 (C–OH), 146.9, 146.3,
144.4, 144.3, 142.6, 129.4, 127.9, 127.7, 127.3, 126.0, 125.9, 125.6, 113.9
(Ar–C), 55.3 (O–CH3), 34.1, 32.6, 31.6, 31.5, 29.8 (ArCH2Ar, –OCH3, t-Bu). MS
(FAB): calcd for C41H50O5, M+: 622.37; found: 622.85. Compound 5a: Yield:
45% as a white solid. Rf: 0.83. Mp: Decomposed >240 °C. IR (KBr)
mmax: 3173,
2963, 1259, 1051 cmÀ1 1H NMR (300 MHz, CDCl3): d 10.04 (s, OH, 4H), 7.04
.
(s, ArH, 4H), 6.52 (s, ArH, 4H), 4.23 (d, J = 13.2 Hz, ArCH2Ar, 4H,), 3.62 (s,
OMe, 6H), 3.43 (d, J = 14.7 Hz, ArCH2Ar, 4H,), 1.24 (s, t-Bu, 18H). 13C NMR
(125 MHz, CDCl3): d 154.0, 147.1, 144.7, 144.4, 142.2, 132.4, 130.8, 129.8,
129.2, 128.8, 128.3, 128.1, 127.3, 125.7, 113.9, 55.9, 55.2 (–OCH3), 34.0, 32.4,
31.5, 30.6, 29.7, 27.7, 21.6, 19.2. MS (FAB): calcd for C38H44O6, M+: 596.31;
found: 596.23. Compound 6: Yield: 15% as a brown semi-solid. Rf: 0.30. 1H
NMR (300 MHz, CDCl3): d 10.25 (s, OH, 4H), 7.70 (d, J = 8.3 Hz, ArH tolyl,
2H), 7.32 (m, ArH tolyl, 2H), 7.05 (m, ArH, 4H), 6.91 (s, ArH, 2H), 6.68 (m,
ArH, 2H), 4.20 (br s, ArCH2Ar, 4H), 3.44 (br s, ArCH2Ar, 4H), 2.46 (s, CH3,
3H), 1.20 (s, t-Bu, 18H), 1.19 (s, t-Bu, 9H). 13C NMR (125 MHz, CDCl3): d
149.7, 148.2, 146.8, 146.2, 144.5, 142.7, 134.2, 129.6, 127.9, 127.6, 127.5,
127.1, 126.1, 125.9, 125.6, 123.3, 115.5, 56.0, 34.4, 34.0, 32.5, 32.3, 31.9,
31.5, 31.3, 31.1, 30.7, 29.7, 29.4, 26.9, 22.7, 14.1. MS (FAB): calcd for
C47H54O7S, M+: 762.36; found: 762.77.
Acknowledgements
The authors thank the Council of Scientific and Industrial Re-
search, (NWP 0023), University Grants Commission (UGC) and
the Department of Science and Technology (DST), New Delhi for
financial assistance. We thank Dr. G. Vijay Nair for his valuable
suggestions. Thanks are also due to Ms. Saumini Mathew and Ms.
S. Viji for NMR and mass spectral data.
Supplementary data
19. Jaime, C.; de Mendoza, J.; Prados, P.; Neito, P. M.; Sanchez, C. J. Org. Chem. 1991,
56, 3372.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.118.
20. Procedure for the synthesis of 5-hydroxycalix[4]arene (7): 7,11,23-Tri-tert-butyl-
5-methoxycalix[4]arene, 4a (50 mg, 0.08 mmol) was dissolved in 10 mL of dry
dichloromethane and cooled in an ice-salt mixture. BBr3 (30 mg, 0.12 mmol)
was added over a period of 0.5 h and the reaction mixture was allowed to stir
under argon for 3 h (0 °C). The extent of reaction was tested by TLC. The
reaction mixture was worked-up using dichloromethane–water mixture and
the product was obtained using column chromatography [petroleum ether–
ethyl acetate (90:10)] as a colourless semi solid 7 (36 mg, 75%). Rf: 0.65. IR
References and notes
1. For reviews on calixarenes see: (a) Gutsche, C. D. Calixarenes; Royal Society of
Chemistry: Cambridge, 1989; (b) Böhmer, V. Angew. Chem., Int. Ed. Engl. 1995,
34, 713; (c) Gutsche, C. D. Calixarenes Revisited; Royal Society of Chemistry:
Cambridge, 1998; (d)Calixarenes 2001; Asfari, Z., Böhmer, V., Harrowfield, J.,
Vicens, J., Eds.; Kluwer Academic: Dordrecht, 2001.
(KBr) m .
max: 3173, 2960, 2858, 1786, 1060 cmÀ1 1H NMR (300 MHz, CDCl3): d
10.20 (s, OH, 4H), 7.04 (m, ArH, 6H), 6.53 (s, ArH, 2H), 4.10 (br s, ArCH2Ar, 4H),
3.32 (br s, ArCH2Ar, 4H), 1.22 (s, t-Bu, 18H), 1.19 (s, t-Bu, 9H), one of the OH
protons could not be detected. 13C NMR (75 MHz, CDCl3): 153.9 (C–OH), 146.9,
146.3, 144.4, 144.3, 142.6, 129.4, 127.9, 127.7, 127.3, 126.0, 125.9, 125.6, 113.9
(Ar–C), 34.1, 32.6, 31.6, 31.5, 29.8 (ArCH2Ar, t-Bu). MS (FAB): calcd for
C40H48O5, [M+1]+: 609.81; found: 609.92.
2. Litwak, A. M.; Biali, S. E. J. Org. Chem. 1992, 57, 1945.
3. (a) Görmar, G.; Seiffarth, K.; Schultz, M.; Zimmerman, J.; Flamig, G.
Macromol. Chem. 1990, 191, 81; (b) Middel, O.; Greff, Z.; Taylor, N. J.;
Verboom, W.; Reinhoudt, D. N.; Snieckus, V. J. Org. Chem. 2000, 65, 667; (c)
Agbaria, K.; Biali, S. E. J. Am. Chem. Soc. 2001, 123, 12495; (d) Simaan, S.;
Agbaria, K.; Biali, S. E. J. Org. Chem. 2002, 67, 6136; (e) Simaan, S.; Biali, S. E.
J. Org. Chem. 2004, 69, 95.
21. Lee, M.-D.; Yang, K.-M.; Tsoo, C.-Y.; Shu, C.-M.; Lin, L.-G. Tetrahedron 2001, 57,
8095.