A novel synthesis of parent resorc[4]arene and its partial alkyl ethers

Article abstract of DOI:10.1016/j.tetlet.2004.01.080

Treatment of 2,4-diisopropoxybenzyl alcohol with chlorotrimethylsilane in acetonitrile at room temperature for 1h afforded a novel crystalline resorc[4]arene octaisopropyl ether in 96% yield. Protecting groups were cleaved by boron trichloride in dichloromethane within 30min and the parent resorc[4]arene was isolated by flash chromatography in 76% yield. The outcome of the deprotection step was dependent on the conditions used as it is exemplified by a preparation of resorc[4]arene heptaisopropyl ether.

Full text of DOI:10.1016/j.tetlet.2004.01.080

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2043–2046
A novel synthesis of parent resorc[4]arene and its partial
alkyl ethers
Jan Stursa,a Hana Dvorakova,b Jan Smidrkal,c Hana Petrickovad and Jitka Moravcovaa,*
aDepartment of Chemistry of Natural Compounds, Institute of Chemical Technology, Technicka 5, CZ-166 28Prague 6,
Czech Republic
bLaboratory of NMR Spectroscopy, Institute of Chemical Technology, Technicka 5, CZ-166 28Prague 6, Czech Republic
cDepartment of Dairy Chemistry and Technology, Institute of Chemical Technology, Technicka 5, CZ-166 28Prague 6, Czech Republic
dDepartment of Solid State Chemistry, Institute of Chemical Technology, Technicka 5, CZ-166 28Prague 6, Czech Republic
Received 4 December 2003; revised 5 January2004; accepted 19 January2004
Abstract—Treatment of 2,4-diisopropoxybenzyl alcohol with chlorotrimethylsilane in acetonitrile at room temperature for 1 h
afforded a novel crystalline resorc[4]arene octaisopropyl ether in 96% yield. Protecting groups were cleaved by boron trichloride in
dichloromethane within 30 min and the parent resorc[4]arene was isolated byflash chromatographyin 76% yield. The outcome of
the deprotection step was dependent on the conditions used as it is exemplified bya preparation of resorc[4]arene heptaisopropyl
ether.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The acid-catalyzed condensation reaction between res-
orcinol and benzaldehyde was first reported1 byBayer in
1872 and the correct structure of the product,
resorc[4]arene, was elucidated byErdtman onlyin
1968.2 Since that time, the readilyavailable C-alkylated
calixresorcinarenes have been found to possess inter-
More recently, octamethyl and octa-allyl ethers 2 and 5
were obtained from the cyclooligomerization of the
corresponding 2,4-bis(alkoxy)benzyl alcohols in the
presence of scandium trifluoromethanesulfonate.6 The
yields of 2 and 5 were 34% and 54%, respectively. Octa-
allyl ether 5 was then deprotected using PdCl2(PPh3)2
and ammonium formate and the resorc[4]arene 1 was
isolated in 52% yield. The condensation of 1,3-dimeth-
oxybenzene with paraformaldehyde in 2-ethoxyethanol
was reported to produce octamethyl ether 2 as a
mixture of stereoisomers, which were separated due to
their different solubilities in chloroform.7 Both isomers
of 2 were prepared in 82% yield. However, the low
overall yields of resorc[4]arene 1 seem to be serious
drawbacks of the time consuming syntheses reported so
far.
esting material and complexation properties and their
3
chemistryhas been well established.
However, the
parent resorc[4]arene 1 cannot be synthesized by this
method due to the high reactivityof formaldehdye
resulting in polymer formation. Thus, several alternative
routes had to be developed. A treatment of 2,4-
dimethoxybenzyl alcohol with trifluoroacetic acid at
ambient temperature for 18 h led to resorc[4]arene
octamethyl ether 2 in 95% yield.4 Subsequent depro-
tection with boron tribromide followed byacetylation
afforded the octaacetate 3 in 25% yield. The reaction of
2-propylresorcinol with formaldehyde diethyl acetal
gave
a mixture of three cyclic oligomers where
R3
4
resorc[4]arene 4 was a major product after 6 h.5
R1O
OR2
1, R1 = R2 = R3 = H
2, R1 = R2 = CH3, R3 = H
R1O
R3
R1O
OR1
R3
3, R1 = R2 = COCH3, R3 = H
1
4, R1 = R2 = H, R3 = CH2CH2CH3
5, R1 = R2 = CH2CH=CH2, R3 = H
6, R1 = R2 = (CH3)2CH, R3 = H
7, R1 = (CH3)2CH, R2 = R3 = H
OR1
Keywords: Resorc[4]arene; 2,4-Diisopropoxybenzyl alcohol; Lewis
acid; Conformation; Partiallyalkylated resorc[4]arene.
* Corresponding author. Tel.: +420-224-354-283; fax: +420-224-310-
859; e-mail: jitka.moravcova@vscht.cz
R1O
OR1
R3
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.080

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J. Stursa et al. / Tetrahedron Letters 45 (2004) 2043–2046
We describe herein an efficient and expedient synthetic
route to resorc[4]arene 1 based on the observation that
2,4-diisopropoxybenzyl alcohol underwent quantitative
tetramerization in the presence of chlorotrimethylsilane.
The effect of a Lewis acid on the cyclooligomerization of
2,4-bis(alkoxy)benzyl alcohols6 and 2,4-dimethoxycin-
namate8 has alreadybeen assessed but chlorotrimethyl-
silane seems to be the most efficient reagent with its low
price making it suitable for large-scale operations.
Commercially available 2,4-dihydroxybenzaldehyde was
alkylated with isopropyl bromide under phase transfer
catalysis (Scheme 1). 2,4-Diisopropoxybenzaldehyde
1
was obtained in 90% yield and identified9 from its H
NMR spectrum. Its subsequent reduction with sodium
borohydride gave 2,4-diisopropoxybenzyl alcohol in
94% yield.10 Cyclooligomerization of 2,4-diisopro-
poxybenzyl alcohol was carried out in several solvents
(acetonitrile,
N,N0-dimethylformamide,
dichloro-
methane) in the presence of a mineral acid (sulfuric or
hydrochloric acid), trifluoroacetic acid or a Lewis acid
(boron trifluoride diethyl etherate or chlorotrimethyl-
silane). In all these investigations, resorc[4]arene octa-
isopropyl ether 6 was formed as indicated byTLC.
However, the complexityof the reaction mixture was
dependent on the ratio of the reagents, temperature and
duration of the reaction. As the highest yield and sim-
plest purification of resorc[4]arene 6 on a multigram
scale were required, chlorotrimethylsilane and aceto-
nitrile were then selected as the conditions of choice.
Thus, the tetramerization of 2,4-diisopropoxy-
benzyl alcohol spontaneously afforded crystalline
resorc[4]arene 6 in 96% yield11 within 1 h at room tem-
perature.12 The structure of 6 was proven unequivocally
by X-ray crystallography and mass spectrometry.
Resorc[4]arene 6 crystallized easily yielding single crys-
Figure 1. X-raycrystal structure of resorcinarene 6.
ible species on the NMR time scale. Nevertheless, the
NOE connectivities observed between the CH proton of
the isopropyl groups and the aromatic proton H-1
suggest that the preferred conformation of 6 is more
likelyto be the 1,3-alternate one. For a deeper under-
standings of its conformational behaviour, temperature-
1
dependent H NMR spectroscopywas used. There was
no significant change in the 1H NMR spectra within the
accessible temperature range in CD2Cl2 (173–308 K).
The protecting groups in resorc[4]arene 6 were smoothly
cleaved with boron trichloride and the parent re-
sorc[4]arene 1 was isolated byflash chromatographyin
76% yield.16 Both 1H and 13C NMR spectra of re-
sorc[4]arene 1 in CD3OD were identical with those
described.6 As observed for the protected compound 6,
the temperature-dependent 1H NMR spectra of re-
sorc[4]arene 1 did not reveal significant changes when
measured in CD3OD (193–298 K). These results suggest
either a conformationallyflexible structure or the 1,3-
alternate conformation. However, taking into consider-
ation the possibilityof intramolecular hydrogen bonds
being able to stabilize the cone conformation or to
generate molecular capsules,17 further NMR investiga-
tions are in progress.
13–15
tals of good qualityfrom acetonitrile solution.
Novel resorc[4]arene 6 occupied the 1,3-alternate con-
formation in the solid state (Fig. 1). Furthermore, the
structure of 6 in solution was studied byNMR spec-
troscopy. In accord with the previously reported octa-
methyl4 and octa-allyl6 ethers, 1H and 13C NMR spectra
in CDCl3 indicated either the 1,3-alternate conformation
or a fast equilibrium among the conformationallyflex-
CHO
O
CHO
OH
O
OH
b
a
During deprotection of resorc[4]arene 6 we found that
the isopropyl groups could be removed stepwise and the
ratio of partiallyalkylated derivatives of resorc[4]arene 1
depended on the conditions used. Thus, treatment of
resorc[4]arene 6 with boron trichloride (4 equiv) at 0 ꢁC
for 30 min gave a complex mixture from which
resorc[4]arene heptaisopropyl ether 7 was isolated in
18% yield and its identity was confirmed by MS and
NMR studies.18
OH
O
c
d
6
1
O
Scheme 1. Reagents and conditions: (a) iPrBr (3.5 equiv), K2CO3
(2 equiv), Bu4NþIÀ, acetone, 80 ꢁC, 18 h; (b) NaBH4 (0.5 equiv), eth-
anol/water (2:1, v/v), rt, 1 h; (c) (CH3)3SiCl (2.5 equiv), acetonitrile, rt,
1 h; (d) BCl3 (15 equiv), CH2Cl2, 0 ꢁC, 1 h.
PartiallyO-alkylated C-alkyl resorcinarenes were pre-
pared in good yields by a Lewis acid catalyzed reaction

J. Stursa et al. / Tetrahedron Letters 45 (2004) 2043–2046
2045
of 3-methoxyphenol with octanal19 or 3-cyclopentyl-
oxyphenol with 1,1-dimethoxyhexane.20 In both cases,
the reaction proceeded with remarkable regioselectivity
and the corresponding C4-symmetric resorc[4]arene tetra-
alkyl ether was isolated. Several monoalkyl ethers of
calix[4]arene, obtained either via selective dealkylation21
or partial alkylation,22 have also been reported. In
contrast, partiallyalkylated derivatives of resorc[4]arene
1 have not yet been described. Although selective
deprotection of octaisopropyl ether 6 gave a mixture of
at least six partiallyalkylated products, we were able to
separate five of them byflash chromatographyon silica
gel. The identification of a number and the position of
isopropyl groups employing NMR experiments forms a
part of our ongoing work in this area.
10. Selected analytical data for 2,4-diisopropoxybenzyl alco-
hol: 1H NMR (400 MHz, CDCl3) d 7.12 (d, 1H, Harom
J ¼ 8:0 Hz), 6.45 (s, 1H, Harom), 6.41 (d, 1H, Harom
,
,
J ¼ 8:0 Hz), 4.58 (s, 2H, CH2), 4.55–4.50 (m, 2H, CH,
J ¼ 6:1 Hz), 2.50 (s, 1H, OH), 1.35 (d, 6H, CH3,
J ¼ 6:1 Hz), 1.32 (d, 6H, CH3, J ¼ 6:1 Hz). 13C NMR
(100 MHz, CDCl3) d 158.6, 156.8, 129.5, 122.5, 106.0,
102.3, 70.1, 69.9, 61.9, 22.0, 21.9.
1
11. Selected analytical data for 6: mp 169–170 ꢁC. H NMR
(500 MHz, CDCl3) d 6.43 (s, 4H, H-4), 6.34 (s, 4H, H-1),
4.35 (sept, 8H, J ¼ 6:0 Hz, CH(CH3)2), 3.71 (s, 8H, CH2),
1.26 (d, 48 H, J ¼ 6:0 Hz, CH(CH3)2). 13C NMR
(125.8 MHz, CDCl3) d 154.28 (C-3), 131.41 (C-1), 123.65
(C-2), 103.00 (C-4), 71.24 (CH(CH3)2), 27.99 (CH2), 22.33
(CH(CH3)2). Anal. calcd for C52H72O8 (825.14): C, 75.69;
H, 8.80; Found: C, 75.36; H, 8.72.
12. Optimized procedure: 2,4-Diisopropoxybenzyl alcohol
(13.3 g, 59 mmol) was dissolved in CH3CN (29 mL) and
chlorotrimethylsilane (20 mL, 158 mmol) was added in one
portion. The mixture turned violet immediatelyand was
allowed to stand at room temperature for 1 h. Crystals of
resorc[4]arene 6 were filtered off, washed with CH3CN and
dried under vacuum (11.7 g, 96%).
In conclusion, we have established that cyclooligomer-
ization of 2,4-diisopropoxybenzyl alcohol in the pres-
ence of chlorotrimethylsilane followed by deprotection
represents a simple and effective route to the parent
resorc[4]arene which was isolated in 73% overall yield.
Furthermore, it is expected that partial deprotection of
resorc[4]arene octaisopropyl ether 6 could offer a wayin
which resorc[4]arene can be functionalized selectively.
Thus tailoring of different types of selectively function-
alized resorc[4]arenes enables the synthesis of new types
of receptors with enhanced selectivityand geometrical
stability. Our initial study shows its feasibility and
demonstrates this verypromising approach.
13. C52H72O8, MW 825.136, monoclinic system, space group
P121/n1,
a ¼ 15:0660ð2Þ,
b ¼ 22:6530ð4Þ,
c ¼
3
ꢀ
ꢀ
15:8310ð2Þ A, b ¼ 113:57ð4Þ, V ¼ 4952:2ð1Þ A , Z ¼ 4,
Dc ¼ 1:1067 g cmÀ3
,
lðMoKaÞ ¼ 0:729 cmÀ1
,
crystal
dimensions of 0.4 · 0.5 · 0.6 mm. Data were measured at
150 K on a KappaCCD diffractometer with graphite
ꢀ
monochromated MoKa radiation (k ¼ 0:710730 A). The
14
structure was solved bydirect methods
and anisotrop-
icallyrefined byfull matrix least-squares on F values15 to
final R ¼ 0:045, Rw ¼ 0:054 and S ¼ 1:112 with 568
parameters
using
7775
independent
reflections
(hrange ¼ 1:73–27:5). Hydrogen atoms were located from
the expected geometryand were not refined. Crystallo-
graphic data were deposited in CSD under CCDC
registration number 217280.
Acknowledgements
We thank Dr. Pavel Lhotak for valuable discussions and
Dr. David Sykora for MS measurements. This work was
carried out within the frame of a project of the Ministry
of Education, Youth and Sports of the Czech Republic
No. 223300006.
14. Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi,
A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl.
Crystallogr. 1994, 27, 435–435.
15. Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout,
K.; Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487–
1487.
16. Selected analytical data for 1: 1H NMR (500 MHz,
CD3OD) d 6.87 (s, 4H, H-1), 6.26 (s, 4H, H-4), 3.63 (s,
8H, CH2). 13C NMR (125.8 MHz, CD3OD) d 153.80 (C-
2), 132.69 (C-1), 121.85 (C-2), 104.02 (C-4), 29.99 (CH2).
HRMS (ESI) for C28H23O8 (M)1)À: Calcd 487.1390;
Found. 487.1755.
17. For a few recent examples see: Avram, L.; Cohen, Y. Org.
Lett. 2002, 4, 4365–4368; Atwood, J. L. J. Am. Chem. Soc.
2002, 124, 10646–10647; Avram, L.; Cohen, Y. J. Am.
Chem. Soc. 2002, 124, 15148–15149; Atwood, J. L.;
Barbour, L. J.; Jerga, A. Chem. Commun. 2001, 2376–
2377.
References and notes
1. Bayer, A. Ber. Dtsch. Chem. Ges. 1872, 5, 25–26.
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1679–1682.
3. Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Tetra-
hedron 1996, 52, 2663–2704; Bohmer, V. Angew. Chem.
Int. Ed. Engl. 1995, 34, 713–745.
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Morikawa, O. Tetrahedron Lett. 1996, 37, 7383–7386.
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O. J. Chem. Soc., Perkin Trans. 1 1999, 2583–2584.
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Polym. Bull. 2002, 47, 493–499; Li, D.; Suzuki, T.;
Konishi, G. I.; Yamagishi, T. A.; Nakamoto, Y. Polym.
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8. Botta, B.; Iacomacci, P.; Di Giovanni, C.; Monache, G.
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Soc., Perkin Trans. 1 2000, 5, 799–811.
18. Selected analytical data for 7: 1H NMR (500 MHz,
CDCl3) d 6.99 (br s, 1H, OH), 6.70 (s, 1H, arom), 6.68
(s, 2H, arom), 6.51 (s, 1H, arom), 6.49 (s, 2H, arom), 6.46
(s, 1H, arom), 6.39 (s, 1H, arom), 4.62 (sept, 1H,
J ¼ 6:0 Hz, CH(CH3)2), 4.50–4.30 (m, 6H, J ¼ 6:0 Hz,
CH(CH3)2), 3.76 (s, 2H, CH2), 3.75 (s, 4H, 2 · CH2), 3.62
(s, 2H, CH2), 1.45 (d, 6 H, J ¼ 6:0 Hz, CH(CH3)2), 1.36–
1.30 (3 · d, 18H, J ¼ 6:0 Hz, 3 · CH(CH3)2), 1.29–1.20
(3 · d, 18H, J ¼ 6:0 Hz, 3 · CH(CH3)2). 13C NMR
(125.8 MHz, CDCl3) d 155.15, 154.56, 154.54, 154.46,
154.01, 153.90, 152.51, 151.53 (C-3 and C-5), 132.74,
131.59, 131.21, 131.11, 129.44 (C-1), 125.39, 124.37,
123.81, 123.73, 122.87, 122.50, 122.00, 118.90 (C-2 and

2046
J. Stursa et al. / Tetrahedron Letters 45 (2004) 2043–2046
C-6), 103.14, 102.76, 102.35, 101, 38 (C-4), 71.64, 71.53,
20. Boxhall, J. Y.; Page, P. C. B.; Elsegood, M. R. J.; Chan,
Y.; Heaney, H. Synlett 2003, 7, 1002–1006.
21. Casnati, A.; Arduini, A.; Ghidini, E.; Pochini, A.; Ungaro,
R. Tetrahedron 1991, 47, 2221–2228.
22. Groenen, L. C.; Ruel, B. H. M.; Verboom, W.; Pochini,
A.; Ungaro, R.; Reinhoudt, D. N. Tetrahedron 1991, 47,
8379–8384.
71.28, 71.12, 70.89, 70.48 (CH(CH3)2), 29.39, 28.58, 27.20,
27.01 (CH2), 22.25, 22.22, 22.20, 22.13, 22.05, 21.87
(CH(CH3)2). HRMS (ESI) for C49H65O8 (M)1)À: Calcd
781.4680; Found. 781.4761.
19. McIldowie, M. J.; Mocerino, M.; Skelton, B. W.; White,
A. H. Org. Lett. 2000, 2, 3869–3971.