Synthesis of Monofunctionalized Calix[5]arenes

Article abstract of DOI:10.1055/s-0036-1589127

Seven OH-free and O -permethylated monofunctionalized calix[5]arenes carrying either additional methyl or tert -butyl groups are prepared following fragment condensation protocols. This strategy proves to be superior to previous approaches. Calix[5]arenes with free OH groups all adopt a cone conformation stabilized by a seam of hydrogen bonds at the lower rim. Post-condensation modifications, i.e., methylation of phenolic OH groups or functional group interconversions can also be achieved. Bulky tert -butyl groups are also found to stabilize the cone conformations of O -methylated compounds. These compounds offer versatile functional groups that make these concave molecules interesting building blocks for the synthesis of more sophisticated molecular architectures.

Full text of DOI:10.1055/s-0036-1589127

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–I
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B. Ingenfeld et al.
Paper
Synthesis
Synthesis of Monofunctionalized Calix[5]arenes
Björn Ingenfeld
Steffen Straub
Christopher Frömbgen
Arne Lützen*
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Universität Bonn, Kekulé-Institut für Organische Chemie und
Biochemie, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
arne.luetzen@uni-bonn.de
Received: 31.08.2017
Accepted after revision: 02.10.2017
Published online: 08.11.2017
tutions.6c,11 Hence, we decided to prepare monofunctional-
ized tetraalkyl calix[5]arenes to provide useful building
blocks for the synthesis of more sophisticated (supra-)
molecular architectures.
DOI: 10.1055/s-0036-1589127; Art ID: ss-2017-z0565-op
Abstract Seven OH-free and O-permethylated monofunctionalized
calix[5]arenes carrying either additional methyl or tert-butyl groups are
prepared following fragment condensation protocols. This strategy
proves to be superior to previous approaches. Calix[5]arenes with free
OH groups all adopt a cone conformation stabilized by a seam of hydro-
gen bonds at the lower rim. Post-condensation modifications, i.e.,
methylation of phenolic OH groups or functional group interconver-
sions can also be achieved. Bulky tert-butyl groups are also found to sta-
bilize the cone conformations of O-methylated compounds. These com-
pounds offer versatile functional groups that make these concave
molecules interesting building blocks for the synthesis of more sophisti-
cated molecular architectures.
In principle, there are three strategies to prepare selec-
tively functionalized calixarenes that have also been em-
ployed to synthesize calix[5]arene derivatives: (i) by pre-
paring a calix[5]arene first and performing a post-cycliza-
tion modification,6c,11 (ii) by preparing a functionalized
linear oligomer and then cyclizing it,12 or (iii) by fragment
condensation of oligomeric building blocks, such as tri-
meric and dimeric or tetrameric and monomeric combina-
tions, to prepare a calix[5]arene.13
Whereas approach (i) works nicely for calix[4]-, ca-
lix[6]-, and calix[8]arenes that carry tert-butyl groups in
para positions relative to the hydroxy functions, which can
be assembled in 50%,14 85%,15 or 78% yield,16 respectively,
this does not really work well for calix[5]- or calix[7]arenes,
which cannot really be prepared in yields higher than 10–
15%.17,18 Since this approach then includes a retro-Friedel–
Crafts alkylation and an additional electrophilic aromatic
substitution, the overall yields are usually way below 3%.6c
Although the second approach (ii) proved to be more
versatile concerning the choice of the alkyl groups on the
aromatic rings and the functionalization of the OH
groups,6d it still suffers from similar low overall yields.
Hence, we decided to follow the fragment condensation
strategy as depicted schematically in Scheme 1, because it
usually provides the desired functionalized calixarenes in
the highest yields.13a,19
Key words concave molecules, cyclophanes, calix[5]arenes, Duff re-
action, fragment condensation strategy
Concave macrocyclic molecules bearing cavities,1 for ex-
ample, cyclodextrins,2 resorcinarenes,3 or calixarenes,3,4 are
important building blocks in supramolecular chemistry.
Among these, the latter are arguably the best studied artifi-
cial cyclophane derivatives. This is definitely true for the te-
trameric calix[4]arenes and the hexameric calix[6]arenes,
which can be accessed rather easily. Unfortunately, the syn-
thesis of calix[5]arenes is not as easy, although the pentam-
er has been reported to have some very interesting recogni-
tion properties toward cesium5 and ammonium ions6 and
toward fullerenes.7 One of these receptors could even be
controlled by an allosteric effect,7d which, due to our inter-
est in the development of artificial allosteric receptors,8,9 is
why calix[5]arenes caught our attention.
Since [3+2]-condensations tend to work slightly better
than the [4+1]-condensations,13a we employed this strategy
first. The necessary dimeric building block 6 was prepared
in 5 steps in 55% overall yield starting from 4-tert-butyl-
phenol (1) as shown in Scheme 2. Therefore, the starting
material was formylated upon treatment with paraform-
To be useful for this purpose it is necessary to prepare
selectively (mostly mono-)functionalized derivatives. Up to
now, however, there are only a few reports on selective O-
alkylations at the phenolic OH functions10 or on aryl substi-
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B. Ingenfeld et al.
Paper
Synthesis
aldehyde and MgCl2 following a protocol reported by
Knight,20 before the resulting aldehyde 2 was reduced to the
corresponding benzylic alcohol 3 employing conditions de-
veloped by Lee.21 Acid-mediated condensation with 1 then
gave 4,22 which was subsequently diformylated to give 5 in
a two-fold Duff reaction.23 Finally, two-fold reduction gave
rise to the desired diol 6.
We then turned our attention to the synthesis of tetra-
functionalized phenols carrying a bromine atom, a nitro, or
an ester group (Scheme 3). Therefore, p-functionalized phe-
nols were subjected to a two-fold Duff reaction following
protocols reported by Lindoy,23 Hrynielwicka,24 and
Routasalo,25 respectively.
OH
OH
OH
OH
OH
HO
OH
+
OH
OH
HMTA, TFA
130 °C, 1–4 d
OHC
CHO
R
X
R
R
R
7: X = Br (56%)
8: X = NO2 (61%)
9: X = CO2Me (87%)
[3+2]
X
X
X
Scheme 3 Synthesis of 2,6-diformylated p-functionalized phenols 7–9
R
R
At this point temperature control turned out to be cru-
cial to succeed: at temperatures in the range of 90–100 °C
we mainly obtained monoformylated products, whereas we
observed polymerization at temperatures >130 °C. It should
also be noted that elongating the reaction time for the syn-
thesis of the bromide 7, unfortunately, did not lead to an in-
crease in the yield.
OH
HO
OH
OH HO
X = functional group
R = alkyl
R
R
[4+1]
Subsequent reduction with either LiAlH4 or NaBH4 went
smoothly to give the desired diols 10–12 in very good yields
as shown in Scheme 4.
OH
R
OH
R
OH
R
OH
OH
HO
OH
+
OH
OH
LiAlH4
THF
2 h, r.t
R
X
OHC
OHC
CHO
CHO
HOH2C
HOH2C
CH2OH
Scheme 1 [3+2]- and [4+1]-fragment condensation strategies for the
synthesis of functionalized calix[5]arenes
10: X = Br (93%)
11: X = NO2 (79%)
X
X
NaBH4
MeOH
0 °C
OH
OH
paraform-
CH2OH
aldehyde
MgCl2, Et3N
MeCN, 3 h, Δ
30 min
OH
OH
OH
LiAlH4, THF
2 h, r.t., 1 h, Δ
CHO
80%
OH
12
CO2Me
CO2Me
95%
98%
1
2
3
Scheme 4 Synthesis of diols 10–12
1, p-TsOH,
120 °C, 3 d
68%
Unfortunately, the two-fold condensation with two
molecules of 4-tert-butylphenol (1) turned out to be unex-
pectedly difficult. We were only able to transfer 10 into the
trimeric building block 13 (Scheme 5) needed for the [3+2]-
condensation with 6 to afford the targeted monobromo-
functionalized calix[5]arene 14 in 25% yield.26
OH
OH
OH
OH
HMTA, TFA
2 d, Δ
OHC
CHO
91%
5
4
This corresponds to an overall yield of 9% starting from
4-bromophenol or 14% starting from 4-t-butylphenol for
this nine-step synthesis, which is significantly higher than
is usually achieved by using any of the other strategies de-
scribed above. However, we have to point out that the con-
centration of the building blocks turned out to be critical
since, at higher concentrations, we observed the formation
of calix[10]arene 15 (Figure 1) as a side product by mass
spectrometric means.27
LiAlH4, THF
2 h, r.t., 1 h, Δ
95%
OH
OH
HO
OH
6
Scheme 2 Synthesis of dimeric building block 6
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B. Ingenfeld et al.
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Synthesis
OH
OH
HOH2C
CH2OH
Br
2
+
1
10
Br
OH
OH
OH
p-TsOH
120 °C, 3 d
OH
OH
69%
14
OH
OH
OH
NaH, MeI, THF,
DMF, 48 h, Δ
92%
Br
13
Br
6, p-TsOH, toluene
Δ, 3.5 d
25%
O
O
O
O
O
Br
16
Scheme 6 Synthesis of hexamethyl ether 16
OH
HO
OH
OH
OH
OH
OH HO
HO
OH
2
+
14
1
6
p-TsOH
120 °C, 3 d
72%
Scheme 5 Synthesis of bromine-functionalized calix[5]arene 14 via
[3+2]-fragment condensation of building blocks 6 and 13
OH
OH
OH
OH
Br
Br
17
OH
OH
OH
OH
10, p-TsOH, toluene
Δ, 3.5 d
OH
OH
14%
OH
OH
OH
OH
15
Figure 1 Difunctionalized calix[10]arene 15
Br
Calix[5]arene 14 adopts a cone conformation as re-
vealed by analysis of the NMR spectra (see the Supporting
Information). The same is true for its derivative 16, ob-
tained upon permethylation of the hydroxy functions ac-
cording to the protocol of Gutsche (Scheme 6).28
OH
OH
OH
OH
OH
14
Scheme 7 Synthesis of calix[5]arene 14 via [4+1]-fragment condensa-
tion of building blocks 10 and 17
We then decided also to explore the [4+1]-fragment
condensation for comparison. Therefore, we first prepared
tetrameric building block 17 in 72% yield from the two-fold
condensation of 6 with 4-t-butylphenol (1) followed by a
macrocyclization upon treatment of 17 with bromide 10
(Scheme 7). This sequence also gave target compound 14,
however, in only 14% yield, which corresponds to an overall
yield of a little more than 7% starting from 4-bromophenol.
Hence, this way proved slightly less efficient than the [3+2]-
fragment condensation.
Nevertheless, it proved successful for the synthesis of
the desired nitro-functionalized calix[5]arene 18, which
could be prepared in 10% yield upon reaction of 17 with 11,
corresponding to an overall yield of a little more than 4%
starting from 4-nitrophenol. Again, calix[5]arene 18 could
be successfully permethylated by Gutsche’s protocol28 to
give the pentamethyl ether 19 (Scheme 8). Like the
bromine-functionalized calix[5]arenes, the nitro-derivatives
18 and 19 also adopt cone conformations.
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B. Ingenfeld et al.
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Whereas OH-free calix[5]arene 20 also adopts a cone
conformation stabilized by a seam of hydrogen bonds, pen-
tamethyl ether 21 behaves different. Due to the lack of sta-
bilizing hydrogen bonds and the less bulky methyl groups
instead of the tert-butyl groups in 16 and 19, permethylat-
ed 21 is conformationally much more flexible and adopts at
least two different conformations at room temperature, as
revealed by rather complicated NMR spectra.
p-TsOH
toluene
Δ, 3.5 d
NO2
17
+
10%
11
OH
OH
OH
OH
OH
18
NaH, MeI, THF,
DMF, 48 h, Δ
55%
Finally, we explored the potential of 16 with regard to
the synthesis of other functionalized calix[5]arenes via bro-
mine–lithium exchange and subsequent quenching with an
electrophile. Exemplarily, this was tested with tosyl azide
as the electrophile and gave the corresponding azide 29 in
very good yield (Scheme 10) that again adopted a single
cone-shaped conformation.
NO2
O
O
O
O
O
19
In conclusion, we have successfully prepared a series of
seven OH-free and O-permethylated monofunctionalized
calix[5]arenes carrying either additional methyl or tert-bu-
tyl groups following fragment condensation protocols. In
the case of mono-brominated calix[5]arene 14, we tested a
[3+2] strategy as well as a [4+1] strategy. Calix[5]arenes
with free OH groups all adopt a cone conformation. Bulky
tert-butyl groups were also found to stabilize the cone con-
formations of O-methylated compounds 16, 19, and 29, but
the methyl groups of 21 are obviously too small to prevent
rotation of individual aryl groups, and hence 21 adopts at
least two conformations at room temperature. All of these
Scheme 8 Synthesis of nitro-functionalized calix[5]arenes 18 and 19
Next, we followed a similar approach to prepare mono-
bromo-tetramethylcalix[5]arene 20 as depicted in Scheme
9. Although all the formylation and reduction steps pro-
ceeded smoothly again, all three condensation steps gave
significantly lower yields compared to the corresponding
steps employing the respective tert-butyl derivatives.
Nonetheless, 20 could be isolated and converted into its
pentamethyl ether 21 in excellent yield.
paraform-
aldehyde
MgCl2, Et3N
OH
OH
OH
OH
OH
LiAlH4, THF
2 h, r.t., 1 h, Δ
1, p-TsOH
120 °C, 3 d
CHO
MeCN, 3 h, Δ
OH
84%
97%
52%
22
23
24
25
HMTA, TFA
2 d, Δ
79%
OH
OH
OH
OH
LiAlH4, THF
OHC
CHO
2 h, r.t., 1 h, Δ
HO
OH
92%
27
26
OH
Br
OH
OH
OH
OH
p-TsOH
toluene, Δ, 4 d
HO
OH
+
2
48%
10
22
28
Br
Br
O
p-TsOH
toluene
Δ, 3 d
Br
NaH, MeI, THF
DMF, 48 h, Δ
27
+
4%
quant.
O
O
O
28
OH
OH
O
OH
OH
OH
20
21
Scheme 9 Synthesis of monobromo-tetramethylcalix[5]arenes 20 and 21
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Synthesis
3,3′-Methylenebis[(5-tert-butyl)-2-hydroxybenzaldehyde] (5)
Br
O
2,2′-Methylenebis[4-(tert-butyl)phenol] (4) (3.60 g, 11.5 mmol) and
hexamethylenetetramine (HMTA) (6.46 g, 67.9 mmol, 5.9 equiv) were
dissolved in TFA (20 mL) and stirred for 2 d at 90 °C. After that time,
water (60 mL) was added and the resulting mixture was stirred for 4 h
at 80 °C. The product precipitated from solution, was collected by fil-
tration, washed with water, and dried in vacuo. The product was ob-
tained as a yellow solid.
O
O
O
O
16
1. n-BuLi, THF
–78 °C, 30 min
Yield: 3.87 g (91%); C23H28O4, M = 368.47 g/mol.
81%
The analytical data are in accordance with those reported in the liter-
ature.30
2. TsN3, r.t., 12 h
6,6′-Methylenebis[(4-tert-butyl)-2-(hydroxymethyl)phenol] (6)
N3
LiAlH4 (2.16 g, 57 mmol, 3 equiv) was suspended in anhydrous THF
(50 mL) under an argon atmosphere and stirred for 15 min. After that
time, a solution of 5 (7.00 g, 19 mmol) dissolved in anhydrous THF
(75 mL) was added dropwise over 1 h. The resulting mixture was
stirred for 2 h at r.t. and then heated to reflux for 1 h. After cooling to
r.t., the solution was carefully acidified by addition of 2 M HCl. Water
(100 mL) was added and the resulting mixture stirred for 16 h. The
mixture was extracted with EtOAc (5 × 30 mL). The combined organic
layers were dried over Na2SO4 and the solvents removed in vacuo to
give the desired product as a white solid.
O
O
O
O
O
29
Scheme 10 Synthesis of monoazide-functionalized calix[5]arene 29
compounds offer versatile functional groups that make
these concave molecules interesting building blocks for the
synthesis of more sophisticated molecular architectures
with potential applications as receptors in molecular recog-
nition studies.
Yield: 6.71 g (95%); C23H32O4, M = 372.51 g/mol.
The analytical data are in accordance with those reported in the liter-
ature.31
4-Bromo-2,6-di(hydroxymethyl)phenol (10)
LiAlH4 (2.34 g, 61.7 mmol, 3 equiv) was suspended in anhydrous THF
(50 mL) under an argon atmosphere and stirred for 15 min. After that
time, a solution of 7 (4.68 g, 20.4 mmol) dissolved in anhydrous THF
(40 mL) was added dropwise over 1 h. The resulting mixture was
stirred for 2 h at r.t. and then heated to reflux for 1 h. After cooling the
solution to 0 °C, it was carefully acidified by addition of 2 M HCl. Wa-
ter (150 mL) was added and the mixture was extracted with EtOAc
(3 × 50 mL). The combined organic layers were dried over Na2SO4 and
the solvents removed in vacuo to give the desired product as a yellow
solid.
Solvents were dried, distilled and stored under argon according to
standard procedures. Reactions with air and moisture-sensitive
metalorganic compounds were performed under an argon atmo-
sphere in oven-dried glassware using standard Schlenk techniques.
Thin-layer chromatography was performed on aluminum TLC plates
(silica gel 60 F254) from Merck and the products were visualized under
UV light (254 or 366 nm). Products were purified by column chroma-
tography on Merck silica gel 60 (0.04–0.063 mm). 1H and 13C NMR
spectra were recorded at 298 K using Bruker Avance 500 (500.1 MHz
and 125.8 MHz), Bruker Avance 400 (400.1 MHz and 100.6 MHz), or
Bruker Avance 300 (300.1 and 75.5 MHz) spectrometers, respectively.
1H NMR chemical shifts are reported on the δ scale (ppm) relative to
residual non-deuterated solvent as the internal standard. 13C NMR
chemical shifts are given in δ values (ppm) relative to the deuterated
solvent as the internal standard. Signals were assigned on the basis of
1H, 13C, H,H-COSY, HMQC, and HMBC NMR experiments. For the num-
bering schemes of the nuclei of the individual compounds see the
Supporting Information. Mass spectra were taken on a Finnigan MAT
212 with data system MMS-ICIS (EI) or a Bruker micrOTOF-Q (ESI). El-
emental analyses were carried out with a Heraeus Vario EL. Like other
calixarenes, all new calix[5]arenes and the linear tetramer 17 pre-
sented here melt or decompose at temperatures >250 °C. Chemicals
and reagents obtained from commercial sources were used as re-
ceived. 5-tert-Butyl-2-hydroxybenzaldehyde (2),20 4-tert-butyl-2-
(hydroxymethyl)phenol (3),21 2,2′-methylenebis[4-(tert-butyl)phe-
nol] (4),22 4-bromo-2,6-diformylphenol (7),23 4-nitro-2,6-diformyl-
phenol (8),24 methyl 3,5-diformyl-4-hydroxybenzoate (9),25 methyl 4-
hydroxy-3,5-di(hydroxymethyl)benzoate (12),25 2,2′-[(5-bromo-2-
hydroxy-1,3-phenylene)bis(methylene)]bis(4-tert-butylphenol) (13),13b
and 5-methyl-2-hydroxybenzaldehyde (23)29 were prepared accord-
ing to literature protocols.
Yield: 4.45 g (93%); C8H9BrO3, M = 233.06 g/mol.
The analytical data are in accordance with those reported in the liter-
ature.32
4-Nitro-2,6-di(hydroxymethyl)phenol (11)
LiAlH4 (1.00 g, 26.3 mmol, 2.6 equiv) was suspended in anhydrous
THF (100 mL) under an argon atmosphere and stirred for 15 min. Af-
ter that time, a solution of 8 (2.00 g, 10.2 mmol) dissolved in anhy-
drous THF (60 mL) was added dropwise over 1 h. The resulting mix-
ture was stirred for 2 h at r.t. and then heated to reflux for 1 h. After
cooling the solution to 0 °C, it was carefully acidified by addition of 2
M HCl. Water (150 mL) was added and the mixture was extracted
with EtOAc (3 × 50 mL). The combined organic layers were dried over
Na2SO4 and the solvents removed in vacuo to give the desired product
as a yellow solid.
Yield: 1.61 g (79%); C8H9NO5, M = 199.16 g/mol.
The analytical data are in accordance with those reported in the liter-
ature.33
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B. Ingenfeld et al.
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Synthesis
5-Bromo-31,32,33,34,35-pentahydroxy-11,17,23,29-tetra(tert-
HRMS (ESI, +): m/z [M + Na]+ calcd for C56H7181BrO5Na: 927.4361;
butyl)calix[5]arene (14)
found: 927.4361.
[3+2]-Fragment condensation of 6 and 13: compound 6 (1.65 g, 4.42
mmol), compound 13 (2.20 g, 4.42 mmol, 1 equiv), and p-TsOH (0.05
g, 0.29 mmol) were dissolved in toluene (400 mL) and stirred for 3 d
at 120 °C. The solvent was removed in vacuo and the residue was sub-
jected to column chromatography on silica gel using cyclohex-
ane/CH2Cl2 (1:1) as eluent to give the product as a white solid.
Anal. Calcd for C56H71BrO5·cyclohexane: C, 75.35; H, 8.47. Found: C,
75.40; H, 8.46.
6,6′-Methylenebis{4-(tert-butyl)-2-[5-(tert-butyl)-2-hydroxy-
benzyl]phenol} (17)
Compound 6 (5.00 g, 13.4 mmol), 4-tert-butylphenol (1) (12.00 g,
79.9 mmol, 6 equiv), and p-TsOH (0.30 g, 1.75 mmol) were dissolved
in toluene (100 mL) and heated to reflux for 3 d. Excess 1 was re-
moved by water–steam distillation. The reddish crude product was
purified by column chromatography on silica gel using cyclohex-
ane/EtOAc (1:1) as eluent. The product was obtained as a white solid.
Yield: 0.89 g (24%).
[4+1]-Fragment condensation of 10 and 17: compound 10 (0.73 g,
3.14 mmol), compound 17 (2.00 g, 3.14 mmol), and p-TsOH (0.05 g,
0.29 mmol) were dissolved in toluene (400 mL) and stirred for 3 d at
120 °C. The solvent was removed in vacuo and the residue was sub-
jected to column chromatography on silica gel using cyclohex-
ane/CH2Cl2 (1:1) as eluent to give the product as a white solid.
Yield: 6.14 g (72%); C43H56O4, M = 636.92 g/mol; Rf = 0.46 (cyclohex-
ane/EtOAc, 1:1).
Yield 0.37 g (14%); C51H61BrO5, M = 833.95 g/mol; Rf = 0.82 (cyclohex-
ane/CH2Cl2, 1:1).
The analytical data are in accordance with those reported in the liter-
ature.31
1H NMR (500.1 MHz, CDCl3): δ = 9.04 (s, 1 H, OH-1), 8.69 (s, 2 H, OH-
3), 8.61 (s, 2 H, OH-2), 7.31 (s, 2 H, H-2), 7.22–7.25 (m, 4 H, H-7, H-
11), 7.21 (d, 4J14,18 = 2.4 Hz, 2 H, H-18*), 7.12 (d, 4J14,18 = 2.4 Hz, 2 H, H-
14*), 3.33–4.40 (br s, 10 H, H-5, H-12, H-19), 1.27 (s, 18 H, H-21*),
1.26 (s, 18 H, H-23*) (* assignment of the signals might be inter-
changed).
13C NMR (125.8 MHz, CDCl3): δ = 149.6 (C-4), 147.7 (C-16), 147.6 (C-
9), 144.4 (C-6*), 144.3 (C-13*), 131.6 (C-2), 129.1 (C-3), 126.5 (C-17*),
126.4 (C-10*), 126.4 (C-15*), 126.3 (C-8*), 125.9 (C-11*), 125.8 (C-7*),
125.8 (C-18*), 125.1 (C-14*), 115.5 (C-1), 34.1 (C-20*), 34.0 (C-22*),
31.7 (C-19*), 31.6 (C-12*), 31.6 (C-5*), 31.6 (C-23*), 31.5 (C-21*) (* as-
signment of the signals might be interchanged).
5-Nitro-31,32,33,34,35-pentahydroxy-11,17,23,29-tetra(tert-
butyl)calix[5]arene (18)
Compound 11 (0.35 g, 1.76 mmol), compound 17 (1.00 g, 1.57 mmol),
and p-TsOH (0.05 g, 0.29 mmol) were dissolved in toluene (400 mL)
and stirred for 3 d at 120 °C. The solvent was removed in vacuo and
the residue was subjected to column chromatography on silica gel us-
ing cyclohexane/CH2Cl2 (1:1) as eluent to give the product as a yellow
solid.
Yield 0.13 g (10%); C51H61NO7, M = 800.05 g/mol; Rf = 0.78 (cyclohex-
ane/CH2Cl2, 1:1).
1H NMR (500.1 MHz, CDCl3): δ = 9.87 (s, 1 H, OH-1), 8.64 (s, 2 H, OH-
3), 8.45 (s, 2 H, OH-2), 8.16 (s, 2 H, H-2), 6.97–7.25 (m, 8 H, H-7, H-11,
H-14, H-18), 3.37–4.59 (br s, 10 H, H-5, H-12, H-19), 1.25 (s, 36 H, H-
21, H-23).
13C NMR (125.8 MHz, CDCl3): δ = 156.4 (C-4), 147.5 (C-16*), 147.4 (C-
9*), 144.9 (C-6*), 144.4 (C-13*), 141.7 (C-1), 129.9 (C-2), 128.6 (C-3),
126.6 (C-17), 126.4 (C-10), 126.1 (C-15), 125.9 (C-8), 125.9 (C-11),
125.7 (C-7), 125.3 (C-18), 124.2 (C-14), 34.3 (C-20*), 34.2 (C-22*),
34.1 (C-19), 34.1 (C-12*), 34.0 (C-5*), 31.5 (C-21*), 31.5 (C-23*) (* as-
signment of the signals might be interchanged).
HRMS (ESI, –): m/z [M – H]– calcd for C51H6081BrO5: 833.3613; found:
833.3615.
Anal. Calcd for C51H61BrO5·cyclohexane: C, 74.57; H, 8.01. Found: C,
74.55; H, 8.11.
5-Bromo-31,32,33,34,35-pentamethoxy-11,17,23,29-tetra(tert-
butyl)calix[5]arene (16)
Compound 14 (0.64 g, 0.77 mmol) was dissolved in anhydrous THF
(40 mL) and anhydrous DMF (5 mL) and the solution was cooled to
0 °C. NaH (0.48 g, 20 mmol, 60% in mineral oil) was added, the mix-
ture was stirred for 30 min at r.t. and MeI (5.00 g, 35 mmol) was add-
ed. After heating this mixture to reflux for 2 d, the solvents were re-
moved in vacuo. Water (20 mL) was added to the residue. The precipi-
tate was collected and subjected to column chromatography on silica
gel using cyclohexane/CH2Cl2 (1:1) as eluent to give the desired prod-
uct as a white solid.
HRMS (ESI, +): m/z [M + Na]+ calcd for C51H61NO7Na: 822.4340; found:
822.4343.
5-Nitro-31,32,33,34,35-pentamethoxy-11,17,23,29-tetra(tert-
butyl)calix[5]arene (19)
Compound 18 (0.10 g, 0.12 mmol) was dissolved in anhydrous THF
(20 mL) and anhydrous DMF (2.5 mL) and the solution was cooled to
0 °C. NaH (0.24 g, 10 mmol, 60% in mineral oil) was added, the mix-
ture was stirred for 30 min at r.t. and MeI (5.00 g, 35.2 mmol) was
added. After heating this mixture to reflux for 2 d, the solvents were
removed in vacuo. Water (20 mL) was added to the residue. The pre-
cipitate was collected and subjected to column chromatography on
silica gel using cyclohexane/CH2Cl2 (1:1) as eluent to give the desired
product as a yellow solid.
Yield 0.64 g (92%); C56H71BrO5, M = 904.08 g/mol; Rf = 0.55 (cyclohex-
ane/CH2Cl2, 1:1).
4
1H NMR (500.1 MHz, CDCl3): δ = 7.15 (d, J7,11 = 2.4 Hz, 2 H, H-11),
4
4
7.09 (d, J7,11 = 2.4 Hz, 2 H, H-7), 7.07 (d, J14,18 = 2.5 Hz, 2 H, H-18),
7.02 (s, 2 H, H-2), 6.90 (d, 4J14,18 = 2.5 Hz, 2 H, H-14), 3.83 (br s, 2 H, H-
19), 3.81 (br s, 4 H, H-12), 3.77 (br s, 4 H, H-5), 3.29 (s, 3 H, OCH3-1),
3.13 (s, 6 H, OCH3-3), 2.86 (s, 6 H, OCH3-2), 1.26 (s, 18 H, H-21), 1.15
(s, 18 H, H-23).
Yield 0.06 g (55%); C56H71NO7, M = 870.18 g/mol; Rf = 0.15 (cyclohex-
13C NMR (125.8 MHz, CDCl3): δ = 155.4 (C-4), 154.4 (C-9), 154.1 (C-
16), 145.6 (C-6), 145.4 (C-13), 137.0 (C-3), 134.0 (C-10), 133.8 (C-17),
133.6 (C-15), 133.0 (C-8), 131.2 (C-2), 127.0 (C-11), 126.3 (C-7), 126.3
(C-18), 125.7 (C-14), 115.9 (C-1), 60.6 (C-24), 60.3 (C-26), 60.2 (C-25),
34.2 (C-20), 34.1 (C-22), 33.3 (C-19), 31.8 (C-5), 31.6 (C-21), 31.6 (C-
23), 30.9 (C-12).
ane/CH2Cl2, 1:1).
1H NMR (500.1 MHz, CDCl3): δ = 7.84 (s, 2 H, H-2), 7.18 (s, 2 H, H-11),
7.11 (s, 2 H, H-7), 7.00 (s, 2 H, H-18), 6.86 (s, 2 H, H-14), 3.87 (br s, 4 H,
H-5), 3.83 (br s, 2 H, H-19), 3.81 (br s, 4 H, H-12), 3.33 (s, 3 H, OCH3-1),
3.17 (s, 6 H, OCH3-3), 2.93 (s, 6 H, OCH3-2), 1.27 (s, 18 H, H-21), 1.09
(s, 18 H, H-23).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

G
B. Ingenfeld et al.
Paper
Synthesis
13C NMR (125.8 MHz, CDCl3): δ = 162.0 (C-4), 154.4 (C-9), 154.0 (C-
16), 146.0 (C-6), 145.4 (C-13), 143.3 (C-1), 136.3 (C-3), 134.2 (C-10),
133.8 (C-17), 133.4 (C-15), 132.3 (C-8), 127.4 (C-11), 126.2 (C-7),
126.2 (C-18), 125.4 (C-14), 124.0 (C-2), 61.0 (C-24), 60.4 (C-26), 60.3
(C-25), 34.3 (C-20), 34.0 (C-22), 32.5 (C-19), 31.8 (C-5), 31.6 (C-21),
31.3 (C-23), 31.0 (C-12).
mixture stirred for 16 h. The mixture was extracted with EtOAc
(3 × 50 mL). The combined organic layers were dried over MgSO4 and
the solvents removed in vacuo to give the desired product as a white
solid.
Yield: 7.41 g (97%); C8H10O2, M = 138.17 g/mol.
The analytical data are in accordance with those reported in the liter-
ature.34
HRMS (ESI, +): m/z [M + H]+ calcd for C56H72NO7: 870.5303; found:
870.5303.
2,2′-Methylenebis(4-methylphenol) (25)
5-Bromo-31,32,33,34,35-pentahydroxy-11,17,23,29-tetramethyl-
calix[5]arene (20)
2-(Hydroxymethyl)-4-methylphenol (24) (7.41 g, 53.6 mmol), 4-
methylphenol (22) (17.6 mL, 168 mmol, 3.1 equiv), and p-TsOH (0.30
g, 1.75 mmol) were dissolved in toluene (100 mL) and heated to re-
flux for 4 d. Excess 22 and toluene were removed by distillation under
reduced pressure. The crude product was purified by column chroma-
tography on silica gel using cyclohexane/EtOAc (7:1) as eluent. The
product was obtained as a white solid.
Compound 27 (1.27 g, 4.40 mmol), compound 28 (1.82 g, 4.40 mmol,
1 equiv), and p-TsOH (0.1 g, 0.58 mmol) were dissolved in toluene
(100 mL) and stirred for 3 d at 120 °C. The solvent was removed in
vacuo and the residue was subjected to column chromatography on
silica gel using cyclohexane/CH2Cl2 (2:1) as eluent to give the product
as a white solid.
Yield: 6.36 g (52%); C15H16O2, M = 228.29 g/mol; Rf = 0.22 (cyclohex-
ane/CH2Cl2, 7:1).
Yield 0.115 g (4%); C39H37BrO5, M = 665.62 g/mol; Rf = 0.48 (cyclohex-
ane/CH2Cl2, 2:1).
The analytical data are in accordance with those reported in the liter-
ature.35
1H NMR (500.1 MHz, CDCl3): δ = 9.09 (s, 1 H, OH-1), 8.75 (s, 2 H, OH-
3), 8.68 (s, 2 H, OH-2), 7.30 (s, 2 H, H-2), 6.92–7.22 (m, 8 H, H-7, H-11,
H-14, H-18), 3.33–4.40 (br s, 10 H, H-5, H-12, H-19), 2.22–2.25 (br s,
12 H, H-21, H-23).
13C NMR (125.8 MHz, CDCl3): δ = 149.7 (C-4), 147.9 (C-16*), 147.8 (C-
9*), 131.7 (C-2*), 131.0 (C-6*), 130.8 (C-13*), 130.2 (C-3*), 129.8 (C-
17*), 129.7 (C-10*), 129.7 (C-15*), 129.1 (C-8*), 126.7 (C-11*), 126.6
(C-7*), 126.4 (C-18*), 125.6 (C-14*), 113.3 (C-1), 31.4 (C-19*), 31.3 (C-
12*), 29.8 (C-5*), 20.5 (C-20*), 20.5 (C-21*) (* assignment of the sig-
nals might be interchanged).
3,3′-Methylenebis(2-hydroxy-5-methylbenzaldehyde) (26)
2,2′-Methylenebis(4-methylphenol) (25) (3.00 g, 13.1 mmol) and
hexamethylenetetramine (HMTA) (5.52 g, 39.4 mmol, 3 equiv) were
dissolved in TFA (20 mL) and stirred for 2 d at 90 °C. After that time,
water (60 mL) was added to the orange solution and the resulting
mixture was heated to reflux for 2 h. The product precipitated from
solution, was collected by filtration, washed with water, and dried in
vacuo. The product was recrystallized from a mixture of EtOH and
water (1:1) and obtained as a white solid.
MS (ESI, –): m/z (%) = 665.0 (100) [M – H]–.
Yield: 2.95 g (79%); C17H16O4, M = 284.31 g/mol.
The analytical data are in accordance with those reported in the liter-
ature.36
5-Bromo-31,32,33,34,35-pentamethoxy-11,17,23,29-tetramethyl-
calix[5]arene (21)
Compound 20 (0.06 g, 0.09 mmol) was dissolved in anhydrous THF
(30 mL) and anhydrous DMF (3 mL) and the solution was cooled to
0 °C. NaH (0.04 g, 1.81 mmol, 60% in mineral oil) was added, the mix-
ture was stirred for 30 min at r.t. and MeI (0.45 g, 3.16 mmol) was
added. After heating this mixture to reflux for 2 d, the solvents were
removed in vacuo. Water (30 mL) was added to the residue. The pre-
cipitate was collected and subjected to column chromatography on
silica gel using EtOAc/CH2Cl2 (98:2) as eluent to give the desired prod-
uct as a white solid.
6,6′-Methylenebis[4-methyl-2-(hydroxymethyl)phenol] (27)
LiAlH4 (0.87 g, 22.9 mmol, 3 equiv) was suspended in anhydrous THF
(40 mL) under an argon atmosphere and stirred for 15 min. After that
time, a solution of 26 (2.18 g, 7.67 mmol) dissolved in anhydrous THF
(60 mL) was added dropwise over 1 h. The resulting mixture was
stirred for 2 h at r.t. and then heated to reflux for 1 h. After cooling
down to r.t. again, the solution was carefully acidified by addition of 2
M HCl. Water (200 mL) was added and the resulting mixture stirred
for 16 h. The mixture was extracted with EtOAc (5 × 50 mL). The com-
bined organic layers were dried over MgSO4 and the solvents re-
moved in vacuo to give the desired product as a white solid.
Yield 0.07 g (quant.); C44H47BrO5, M = 735.74 g/mol; Rf = 0.68 (EtOAc/
CH2Cl2, 98:2).
The 1H NMR and 13C NMR (CDCl3, 500.1 and 125.8 MHz, respectively,
see the Supporting Information) spectra are rather complicated due
to an equilibrium of different conformers at r.t. Unfortunately, assign-
ment of individual peaks to individual conformers was not possible
due to severe signal overlapping.
Yield: 2.04 g (92%); C17H20O4, M = 288.34 g/mol.
The analytical data are in accordance with those reported in the liter-
ature.37
MS (ESI, +): m/z (%) = 759.2 (100) [M + Na]+.
2,2′-(5-Bromo-2-hydroxy-1,3-phenylene)bis(4-methylphenol) (28)
Compound 10 (1.65 g, 7.08 mmol), 4-methylphenol (22) (3.82 g, 35.3
mmol, 5 equiv), and p-TsOH (0.10 g, 0.58 mmol) were dissolved in tol-
uene (100 mL) and stirred for 4 d at 120 °C. The solvent and excess 22
were removed in vacuo and the residue was subjected to column
chromatography on silica gel using cyclohexane/CH2Cl2 (6:1) as elu-
ent to give the product as a white solid.
2-(Hydroxymethyl)-4-methylphenol (24)
LiAlH4 (3.37 g, 89 mmol, 1.6 equiv) was suspended in anhydrous THF
(100 mL) under an argon atmosphere and stirred for 15 min. After
that time, a solution of compound 23 (7.50 g, 55.1 mmol) dissolved in
anhydrous THF (60 mL) was added dropwise over 1 h. The resulting
mixture was stirred for 2 h at r.t. and then heated to reflux for 1 h.
After cooling down to r.t. again, the solution was carefully acidified by
addition of 2 M HCl. Water (200 mL) was added and the resulting
Yield 1.39 g (48%); C22H21BrO3, M = 413.13 g/mol; Rf = 0.15 (cyclohex-
ane/CH2Cl2, 6:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I

H
B. Ingenfeld et al.
Paper
Synthesis
The analytical data are in accordance with those reported in the liter-
ature.13b
(5) (a) Izatt, R. M.; Christensen, J. J.; Hawkins, R. T. US Patent
4477377 A, 1984; Chem. Abstr. 1984, 101, 218333 (b) Arnaud-
Neu, F.; Arnecke, R.; Böhmer, V.; Fanni, S.; Gordon, J. L. M.;
Schwing-Weil, M.-J.; Vogt, W. J. Chem. Soc., Perkin Trans. 2 1996,
1855.
5-Azido-31,32,33,34,35-pentamethoxy-11,17,23,29-tetra(tert-
butyl)calix[5]arene (29)
(6) (a) Ferguson, G.; Notti, A.; Pappalardo, S.; Parisi, M. F.; Spek, A. L.
Tetrahedron Lett. 1998, 39, 1965. (b) Choe, J.-I. Bull. Kor. Chem.
Soc. 2003, 24, 75. (c) Ballistreri, F. P.; Notti, A.; Pappalardo, S.;
Parisi, M. F.; Spek, A. L. Org. Lett. 2003, 5, 1071. (d) Garozzo, D.;
Gattuso, G.; Notti, A.; Pappalardo, A.; Pappalardo, S.; Parisi, M.
F.; Perez, M.; Pisagatti, I. Angew. Chem. Int. Ed. 2005, 44, 4892.
(e) Lupo, F.; Capici, C.; Gattuso, G.; Notti, A.; Parisi, M. F.;
Pappalardo, A.; Pappalardo, S.; Gulino, A. Chem. Mater. 2010, 22,
2829.
(7) (a) Haino, T.; Yanase, M.; Kukazawa, Y. Angew. Chem. Int. Ed.
1997, 36, 259. (b) Haino, T.; Yamanaka, Y.; Araki, H.; Fukazawa,
Y. Chem. Commun. 2002, 402. (c) Atwood, J. L.; Barbour, L. J.;
Heavan, M. W.; Raston, C. L. Angew. Chem. Int. Ed. 2003, 42,
3254. (d) Haino, T.; Kobayashi, M.; Chikaraishi, M.; Fukazawa, Y.
Chem. Commun. 2005, 2321. (e) Haino, T.; Fukunaga, C.;
Fukazawa, Y. Org. Lett. 2006, 8, 3545.
Under an argon atmosphere, compound 16 (0.130 g, 0.14 mmol) was
dissolved in anhydrous THF (10 mL). After cooling to –78 °C, n-BuLi
(0.2 mL, 2.5 M in hexane, 0.5 mmol, 3.6 equiv) was added dropwise.
After 30 min, tosyl azide (0.07 mL, 0.47 mmol, 3.4 equiv) mixed with
anhydrous THF (10 mL) was added dropwise. The resulting mixture
was stirred overnight at r.t. Water (10 mL) was added and the aqueous
phase extracted with EtOAc (3 × 25 mL). The combined organic layers
were dried over MgSO4, concentrated in vacuo, and the organic resi-
due subjected to column chromatography on silica gel using cyclo-
hexane/CH2Cl2 (1:1) as eluent to give the product as a yellowish solid.
Yield: 0.10 g (81%); C56H71N3O5, M = 866.20 g/mol; Rf = 050 (cyclohex-
ane/CH2Cl2, 1:1).
4
1H NMR (400.1 MHz, CDCl3): δ = 7.17 (d, J7,11 = 2.4 Hz, 2 H, H-11),
4
4
7.13 (d, J7,11 = 2.4 Hz, 2 H, H-7), 7.05 (d, J14,18 = 2.5 Hz, 2 H, H-18),
6.86 (d, 4J14,18 = 2.5 Hz, 2 H, H-14), 6.54 (s, 2 H, H-2), 3.83 (br s, 2 H, H-
19), 3.82 (br s, 4 H, H-12), 3.79 (br s, 4 H, H-5), 3.39 (s, 3 H, OCH3-1),
3.20 (s, 6 H, OCH3-3), 2.82 (s, 6 H, OCH3-2), 1.30 (s, 18 H, H-21), 1.15
(s, 18 H, H-23).
(8) (a) Shinkai, S.; Sugasaki, A.; Ikeda, M.; Takeuchi, M. Acc. Chem.
Res. 2001, 34, 494. (b) Kovbasyuk, L.; Krämer, R. Chem. Rev.
2004, 104, 3161. (c) Kremer, C.; Lützen, A. Chem. Eur. J. 2013, 19,
6162.
13C NMR (100.6 MHz, CDCl3): δ = 154.5 (C-9), 154.2 (C-16), 153.7 (C-
4), 145.6 (C-6), 145.3 (C-13), 136.4 (C-3), 134.2 (C-1), 134.1 (C-10),
133.7 (C-17), 133.6 (C-15), 133.1 (C-8), 127.1 (C-11), 126.5 (C-7),
126.3 (C-18), 125.4 (C-14), 118.7 (C-2), 60.8 (C-24), 60.4 (C-25), 60.3
(C-26), 34.2 (C-20), 34.1 (C-22), 32.8 (C-19), 31.8 (C-5), 31.6 (C-23),
31.4 (C-21), 30.9 (C-12).
(9) (a) Lützen, A.; Haß, O.; Bruhn, T. Tetrahedron Lett. 2002, 43,
1807. (b) Hass, O.; Schierholt, A.; Jordan, M.; Lützen, A. Synthesis
2006, 519. (c) Zahn, S.; Reckien, W.; Staats, H.; Matthey, J.;
Lützen, A.; Kirchner, B. Chem. Eur. J. 2009, 15, 2572. (d) Staats,
H.; Eggers, F.; Haß, O.; Fahrenkrug, F.; Matthey, J.; Lüning, U.;
Lützen, A. Eur. J. Org. Chem. 2009, 4777. (e) Staats, H.; Lützen, A.
Beilstein J. Org. Chem. 2010, 6, No. 10. (f) Kremer, C.;
Schnakenburg, G.; Lützen, A. Beilstein J. Org. Chem. 2014, 10,
814. (g) Kremer, C.; Lützen, A. Chem. Eur. J. 2014, 20, 8852.
(10) (a) Böhmer, V. Angew. Chem. Int. Ed. 1995, 34, 713.
(b) Pappalardo, S.; Ferguson, F. J. Org. Chem. 1996, 61, 2407.
(11) (a) Arnaud-Neu, F.; Fuangswasdi, S.; Notti, A.; Pappalardo, S.;
Parisi, M. F. Angew. Chem. Int. Ed. 1998, 37, 112. (b) Yanase, M.;
Haino, T.; Fukazawa, Y. Tetrahedron Lett. 1999, 40, 2781.
(c) Haino, T.; Araki, H.; Yamanaka, Y.; Fukazawa, Y. Tetrahedron
Lett. 2001, 42, 3203.
HRMS (ESI, +): m/z [M + Na]+ calcd for C56H71N3O5Na: 888.5286;
found: 888.5303.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589127.
S
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–I