Microwave-assisted synthesis of 1,3-dialkyl ethers of calix[4]arenes: Application to the synthesis of cesium selective calix[4]crown-6 ionophores

Article abstract of DOI:10.1016/j.tetlet.2011.10.142

Partial etherification of phenolic-OH groups of calix[4]arenes with various alkyl halides/tosylates and K₂CO₃ under microwave irradiation afforded 1,3-dialkoxycalix[4]arenes in their cone conformation only as predominant/sole product

Full text of DOI:10.1016/j.tetlet.2011.10.142

Tetrahedron Letters 53 (2012) 141–144
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Tetrahedron Letters
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Microwave-assisted synthesis of 1,3-dialkyl ethers of calix[4]arenes: application
to the synthesis of cesium selective calix[4]crown-6 ionophores
⇑
Sandip K. Nayak , Manoj K. Choudhary
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Partial etherification of phenolic-OH groups of calix[4]arenes with various alkyl halides/tosylates and
K2CO3 under microwave irradiation afforded 1,3-dialkoxycalix[4]arenes in their cone conformation only
as predominant/sole product in good yields (71–85%). The protocol was found to be much superior to
conventional heating both in terms of yield and reaction time. Some of the 1,3-dialkoxycalix[4]arenes
were elaborated further to the syntheses of cesium selective calix[4]crown-6 ionophores.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 9 August 2011
Revised 24 October 2011
Accepted 26 October 2011
Available online 31 October 2011
Keywords:
Microwave irradiation
Calix[4]arene
1,3-Dialkylation
Calix[4]crown-6
The safe treatment and disposal of high level radioactive waste
(HLW) have been the subject of intense research in nuclear indus-
try.1,2 Among the various metal ions present in HLW, ions having
long half life (20–30 years) such as 90Sr and 137Cs, constitute a ma-
jor source of heat in these wastes. Therefore, their removal from an
acidic aqueous solution would greatly simplify handling, storage
and ultimate disposal. Accordingly, intense efforts have been made
for the synthesis of ionophores for selective extraction of 137Cs in
the presence of large concentration of sodium ions present in
nuclear waste.
In recent years, calix[4]arenes have been used as three dimen-
sional molecular building block for the construction of more elab-
orate host molecules with desired properties.3–18 Among them
calix[4]crowns possess preorganized structures and more rigid
binding sites in comparison with calix[4]arene and crown ethers.
They exhibit superior recognition ability toward alkali metal ions
by the cooperative effects of calixarene and crown moieties.19–24
Moreover, their complexing ability not only depends on the length
of the crown ether chain but also on their conformation.19
Earlier, Reinhoudt and co-workers have reported that 1,3-di
(1-octyloxy)-2,4-crown-6-calix[4]arene 1,3-alternate (4a) is highly
efficient for selective extraction of 137Cs ion in the presence of large
quantity of Na+ from highly concentrated nitric acid solution pres-
ent in active nuclear waste.19 In continuation of our quest for the
design and synthesis of ionophores for selective extraction of use-
ful metal ions from nuclear waste, it was of interest to synthesize
4a in larger quantities for the selective separation of cesium from
high level nuclear waste.
Compound 4a was conventionally prepared by the 1,3-distal
dialkylation of phenolic groups of calix[4]arene (1a) to 1,3-dioc-
tyloxycalix[4]arene-cone (3a) in the first step followed by the
introduction of a suitable polyether bridges on the two remaining
OH groups using Cs2CO3 which acts as a template for assuming
1,3-alternate conformation.19 In contrast to the 1,3-dialkylation
of calix[4]arene with reactive electrophlies (CH3Br/I/OTs, BrCH2
CO2R, BrCH2Ph, etc.) which usually take 8–12 h reflux for comple-
tion, the reactions with longer chain alkyl halides (C5 onwards),
however, are very sluggish and the reaction time varies from 5–
6 days. In fact, the reported procedure for the synthesis of 3a needs
5 days refluxing to get moderate yield of the product.19 Moreover,
long time refluxing, necessary for 1,3-dialkylation of 1 with poorly
reactive long chain alkyl halides, often lead to the formation of side
products together with unreacted starting material and thus needs
rigorous column chromatography for purification of the desired
product. This poses a serious hurdle in their large scale synthesis.
Microwave irradiation (MWI) is known to be an important tool
in organic synthesis to improve the selectivity, rate enhancement
and reduction of thermal degradative byproducts.25,26 Keeping this
in view, etherification of calix[4]arene 1a (2 mmol) using 1-iodooc-
tane (6 mmol) and K2CO3 (5 mmol) in acetonitrile was investigated
under MWI (400 W, 63–65 °C). Irradiation of the reaction mixture
for 60 min led to complete consumption of 1a and formation of
two compounds (monitored by TLC). The compounds were sepa-
rated by column chromatography and characterized as cone-ca-
lix[4]arene mono-octyl ether (2a, 36%) and cone-calix[4]arene
1,3-dioctyl ether (3a, 55%)19 by their physical and spectral data
⇑
Corresponding author. Tel: +91 22 25592410; fax: +91 22 25505151.
E-mail address: sknayak@barc.gov.in (S.K. Nayak).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.142

142
S. K. Nayak, M. K. Choudhary / Tetrahedron Letters 53 (2012) 141–144
(Table 1, entry 1). The 1H NMR spectra of 2a displayed three sets of
doublets at d 3.38, 4.20 and 4.29 with coupling constants J = 13.0,
13.7 and 13.7 Hz, respectively, for methylene bridged protons
(ArCH2Ar) while its 13C NMR spectra displayed signals at around
d 31 ppm for the methylene bridge carbons (see the Supplemen-
tary data). This clearly indicates the formation of 2a as cone confor-
mation.27 Similarly, 1H NMR spectra of compound 3a showed a pair
of doublet at d 3.30 (J = 12.9 Hz) and 4.25 (J = 12.9 Hz) and 13C NMR
spectra displayed signals at around d 31 for the methylene bridge
carbons confirming their cone conformation.19 Irradiation of the
reaction mixture for 90 min led to predominant formation of 3a
(74%) along with 2a (11%) (Table 1, entry 2). Further increase in
irradiation time (2.25 h) led to the formation of 3a as sole product
in an 81% yield (Table 1, entry 3). To see the effect of microwave
irradiation, the same reaction was carried out under refluxing
conditions (120 h) when 1a was fully consumed and cone-3a was
obtained as the sole product in a 51% yield (Table 1, entry 4).
To see the scope and generality of the microwave-assisted pro-
tocol for 1,3-dialkylation of calixarenes, etherifications of both 1a
and 1b were carried out with a variety of electrophiles with
K2CO3 as base (Scheme 1). As in the case of 1a, the reaction of 1b
with 1-iodooctane (3.0 equiv) using K2CO3 (2.5 equiv) under MWI
also yielded a mixture of both mono-octyl ether of 4-tert-butylca-
lix[4]arene (2b) and 1,3-dioctyl ether of 4-tert-butylcalix[4]arene
(3b) in 10% and 72% yields, respectively, while 3b was obtained
as the sole product in a 79% yield after irradiation for 2.5 h
(Table 1, entries 5 and 6). When the reaction was carried out under
refluxing conditions (120 h), 3b was obtained in a 49% yield (Table
1, entry 7). Both the compounds 2b and 3b were formed only in
cone conformations; no other conformations were detected. Simi-
larly, reaction of 1a with methyl tosylate under MWI afforded the
1,3-dimethoxycalix[4]arene 3c as the sole product in an 83% yield
(Table 1, entry 9) while the same reaction under refluxing
conditions (16 h) yielded 3c in a 65% yield (Table 1, entry 10). Reac-
tion of 1b with methyl tosylate under MWI afforded the 1,3-dim-
ethoxycalix[4]arene 3c as the sole product in good yield (Table 1,
entry 12). As expected, reaction of 1a with 1-iodopropane yielded
the corresponding 1,3-dialkylated product 3e in good yield (Table
1, entry 14) while 3e was obtained in a 66% yield under reflux
for 24 h (Table 1, entry 15). Similarly reaction of 1b with 1-iodo-
propane yielded the corresponding 1,3-dialkylated products 3f in
good yield (Table 1, entry 16). Importantly, with reactive electro-
philes such as benzyl bromide, ethyl bromoacetate, and bromo ace-
tonitrile, the reaction time under MWI were less and the reaction
completed at a relatively lower power (300 W) to afford the cone
conformer of 1,3-dialkylated ethers (3g–l) as sole product in good
to high yields without the formation of any mono-alkylated prod-
ucts (Table 1, entries 17–22). Furthermore, alkylation of 1a with
20-(2-bromoethoxy)acetophenone afforded 1,3-dialkyl ether (3m)
as sole product in 74% yield (Table 1, entry 23) while the reaction
of 1b with 20-(2-bromoethoxy)acetophenone afforded a mixture of
monoalkylated (2f) and 1,3-dialkylated product (3n) in 4% and 72%
yields, respectively, which on further irradiation yielded 3n as sole
product in a 74% yield (Table 1, entries 24 and 25). The cone
conformation of all the synthesized calix[4]arene ethers was estab-
lished on the basis of their 1H NMR and 13C NMR data.
To see the role of bases on the selective etherification of calixa-
renes under MWI, Cs2CO3 was used in the place of K2CO3. Accord-
ingly, reaction of 1a (1 mmol) with 1-iodooctane (3 mmol) using
Cs2CO3 (2.5 mmol) led to the formation of cone conformer of 3a
as the sole product albeit in moderate yield (44%) along with
unreacted 1a (28%). However, no mono-alkylated product 2a was
detected (Table 1, entry 26). Similarly, reaction of 1a with ethyl
bromoacetate/Cs2CO3 afforded the cone conformer of 3i as a major
product (53%) along with small amount of other alkylated products
(ꢀ5%) and unreacted 1a (16%) (Table 1, entry 27). Thus K2CO3 was
Table 1
Phenolic alkylation of calix[4]arene (1a)/4-tert-butyl calix[4]arene (1b) with alkyl halides/tosylates under microwave irradiationa
Entry
Calix[4]arene
R1X
Power (W)
Time (h)
Product/srefb (% yield)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1a
1a
1a
1b
1b
1a
1a
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1b
1a
1a
C8H17
C8H17
C8H17
C8H17
C8H17
C8H17
C8H17
CH3OTs
CH3OTs
CH3OTs
CH3OTs
I
I
I
I
I
I
I
400
400
1.0
1.5
2.25
120.0
1.5
2.5
120.0
1.5
2.5
16.0
1.5
2.5
1.5
2.0
24.0
1.5
0.5
0.5
0.5
0.5
2a (36)
2a (11)
3a19 (55)
3a (74)
3a (81)
400
Reflux
400
400
Reflux
400
400
Reflux
400
400
400
400
Reflux
400
300
300
300
300
300
300
400
400
—
—
3a (51)
2b27 (10)
3b (72)
3b (79)
3b (49)
3c29 (76)
3c (83)
—
—
2c28 (12)
9
—
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26c
27c
3c (65)
2d (14)
3d29 (71)
3d (77)
3e19 (78)
3e (81)
CH3OTs
C3H7I
C3H7I
C3H7I
—
2e28 (8)
—
—
—
—
—
—
—
—
—
—
2f (4)
—
—
3e (66)
C3H7I
3f30 (80)
3g29 (78)
3h31(83)
3i32 (81)
3j33 (85)
3k34 (76)
3l33 (72)
3m (74)
3n (72)
3n (74)
3a (44)d
3i (53)d,e
C6H5CH2Br
C6H5CH2Br
BrCH2CO2C2H5
BrCH2CO2C2H5
BrCH2CN
0.75
0.75
1.0
1.5
2.0
BrCH2CN
2-(O-C2H4Br)C6H4COCH3
2-(O-C2H4Br)C6H4COCH3
2-(O-C2H4Br)C6H4COCH3
400
400
300
C8H17
I
1.5
0.5
BrCH2CO2C2H5
—
a
b
c
Reaction conditions: calix[4]arene/4-tert-butyl calix[4]arene (2.0 mmol), K2CO3 (5.0 mmol), alkyl halide/tosylate (6.0 mmol), acetonitrile (4 ml) under MWI.
Isolated as cone conformers only, no other conformer/s was detected.
Cs2CO3 (2.5 equiv) was used in place of K2CO3 (2.5 equiv).
d
e
Unreacted 1a was isolated.
Isolated mainly as a cone conformer along with small amount of other conformers (by 1H NMR data).

S. K. Nayak, M. K. Choudhary / Tetrahedron Letters 53 (2012) 141–144
143
R
R
R
R
R
R
R
R
R
R
R
R
K2CO3 (2.5 equiv)
+
R1X (3 equiv)
OR1 OH
R1O
OR1 OH
HO
MWI, 300-400 W, 30-150 min
OH
2
OH
3
HO
OH OH
OH
1
3a: R = H; R1 = C8H17
a: R = H
2a: R = H; R1 = C8H17
2b: R = t-Bu; R1 = C8H17
2c: R = H; R1 = CH3
b: R = t-Bu
3b: R = t-Bu; R1 = C8H17
3c: R = H; R1 = CH3
3d: R = t-Bu; R1 = CH3
3e: R = H; R1 = C3H7
2d: R = t-Bu; R1 = CH3
2e: R = H; R1 = C3H7
3f: R = t-Bu; R1 = C3H7
3g: R = H; R1 = CH2Ph
2f: R = t-Bu; R1 =CH2CH2O-(2-COCH3)C6H4
3h: R = t-Bu; R1 = CH2Ph
3i R = H; R1 = CH2CO2C2H5
3j: R = t-Bu; R1 = CH2CO2C2H5
3k: R = H; R1 = CH2CN
3l: R = t-Bu; R1 = CH2CN
3m: R = H; R1 = CH2CH2O-(2-COCH3)C6H4
3n: R = t-Bu; R1 = CH2CH2O-(2-COCH3)C6H4
Scheme 1. Synthesis of mono- and 1,3-dialkyl ethers of calix[4]arenes under microwave irradiation.
OR
OR
pentaethyleneglycolditosylate
Cs2CO3, ACN, reflux, 10-12 h
O
O
O
O
RO
OH
OR
OH
O
O
a: R = C8H17 (58%)
b: R = C3H7 (79%)
4
1,3-alternate
Scheme 2. Synthesis of cesium ion selective calix[4]crown-6 1,3-alternate ionophores from 1,3-dialkoxy calix[4]arene.
3. Calixarenes in Action; Mandolini, L., Ungaro, R., Eds.; Imperial College Press:
London, 2000.
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Dordrecht, The Netherlands, 2001.
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found to be the base of choice for cone-selective 1,3-dietherifica-
tion of calix[4]arenes under MWI.
Finally, both 1,3-di-n-octyloxycalix[4]arene (3a) and 1,3-di-n-
propyloxy calix[4]arene (3e) were converted into 1,3-di-n-
octyloxycalix[4]arene-crown-619 (4a) and 1,3-di-n-propyloxycalix
[4]arene-crown-619 (4b), respectively, in 1,3-alternate conforma-
tions using Cs2CO3/pentaethyleneglycol ditosylate/acetonitrile
(Scheme 2).
In conclusion, we have developed a microwave-assisted proto-
col for the etherification of phenolic groups of calix[4]arene/
4-tert-butylcalix[4]arene with a variety of elctrophiles (2.5 equiv)
to afford 1,3-dialkoxycalix[4]arenes as major/sole product in good
to high yields. The reaction times were found to be much shorter
(30–150 min) when compared to conventional refluxing condi-
tions which required several hours to days for completion. More-
over there is no need for anhydrous reaction conditions and
calix[4]arene ethers were formed only in cone conformations. Thus
the present protocol will be very useful in the multi-step synthesis
of complex calix[4]arene derivatives as most of those involve
1,3-dietherification in the very first step.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.142.
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