Selective synthesis of "paco" or "alt" isomers of acetoxylcalixarenes catalysed by Bi(OTf)3

Article abstract of DOI:10.3184/030823410X12731611998876

The "paco" or "alt" isomers of acetoxylcalixarenes were selectively prepared in the presence of catalytic amount (2 mol%) of Bi(OTf)₃,. Calix[4]arenes selectively gave two different isomers under specified conditions with a good selectivity, but, calix[6]arenes and calix[8]arenes only gave the "alt" isomers with a high selectivity.

Full text of DOI:10.3184/030823410X12731611998876

250 RESEARCH PAPER
MAY, 250–253
JOURNAL OF CHEMICAL RESEARCH 2010
Selective synthesis of “paco” or “alt” isomers of acetoxylcalixarenes
catalysed by Bi(OTf)3
Can Jin, Youran Wang and Weike Su*
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, P. R. China
The “paco” or “alt” isomers of acetoxylcalixarenes were selectively prepared in the presence of catalytic amount
(2 mol%) of Bi(OTf)3,. Calix[4]arenes selectively gave two different isomers under specified conditions with a good
selectivity, but, calix[6]arenes and calix[8]arenes only gave the “alt” isomers with a high selectivity.
Keywords: stereoselective synthesis, acyloxyl-calixarenes, Bi(OTf)3
Calixarenes and their derivatives are known for their specific
structures.1–3 There are many types of calix[n]arenes (n = 4, 6,
8, etc.). However, calix[4]arenes are the best known and
have four major isomers including cone, partial cone (“paco”),
1,2-alternate (“1,2-alt”), and 1,3-alternate (“1,3-alt”) (Fig. 1)1.
Esterification of the hydroxyl groups of calixarenes was
normally catalysed by acid, such as sulfuric acid,4,5 p-TSA6
and AlCl3,7,8 but the results were not satisfactory giving poor
yields and a low selectivity, and the ratio of two isomers is
ca 1:1.
We now report a novel and convenient method for the
esterification of calixarenes catalysed by metal triflates to
obtain stereoselective products in good yields. In previous
research,9–12 metal triflates have been demonstrated to be
excellent catalysts in many organic reactions. Recently, metal
triflates have attracted much attention due to their low toxicity,
high efficiency and stability13. To the best of our knowledge,
there are no reports of the selective preparation of calix[4]arene
isomers, using catalytic amount of metal triflates.
Table 1 Screening conditionsa
Entry Cat./mol % Solvents Temp./oC Time/h Yieldb/%
1
2
La(OTf)3(2) Ac2O
Zn(OTf)2(2) Ac2O
Yb(OTf)3(2) Ac2O
Yb(OTf)3(2) Ac2O
140
140
140
75
140
50
2
2
45
50
66
70
65
80
75
83
564,5
546
60
78
65
20
60
3
1
4
1
5
Bi(OTf)3(2)
Bi(OTf)3(2)
Bi(OTf)3(2)
Ac2O
Ac2O
Ac2O
1
6
1
7
r.t.
50
1
8
Bi(OTf)3(20) Ac2O
1
9
H2SO4(10)
p-TSA(10)
Bi(OTf)3(2)
Bi(OTf)3(2)
Bi(OTf)3(2)
Bi(OTf)3(2)
Bi(OTf)3(2)
Ac2O
Ac2O
140
140
50
2
10
11
12
13
14
15
20
1
CHCl3
CH2Cl2
Toluene
(CH2)2Cl2
CH3CN
40
1
50
1
50
1
50
1
a All reactions were run with 1.0 mmol 1a under different
reaction conditions.
b Isolated yields of product 2a plus 3a based on 1a.
Firstly, acetylation of p-tert-butyl-calix[4]arene 1a was
chosen as the model reaction to optimise the reaction con-
ditions, including catalysts, solvents, reaction temperature
and time. The result was summarised in Table 1. Most metal
triflates showed a better activity than the traditional catalysts
such as H2SO4 and p-TSA. It was also found that Bi(OTf)3 was
the best (Table 1, Entries 1-6). Further study has shown that a
larger amount (20 mol%) of the Bi(OTf)3 had no significant
influence on the reaction yield (Table 1, Entry 6 and 8), while
higher temperature produced unwanted black solid (Table 1,
Fig. 1 Isomers of calix[4]arene derivatives.
Scheme 1
* Correspondent. E-mail: pharmlab@zjut.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2010 251
Scheme 2
Entry 5). Furthermore, in the presence of 2 mol% Bi(OTf)3,
78% and 80% yields of acetylated products (2a plus 3a) were
obtained in CH2Cl2 or excess Ac2O respectively. If the
reaction was carried out in other solvents, the yields were not
satisfactory.
that under the strong acidic condition (Table 2, entries 1 and 4)
leads to the partial cone conformation, while neutral condi-
tions at higher temperature favour the 1,3-alternate confor-
mation (Table 2, entries 3 and 6).
The two isomers of partial-cone and 1,3-alternate were
1
It should be noted that the catalysts and solvents affected
the conformation of the acetylated product (Scheme 2). When
H2SO4 or p-TSA was used as catalyst, the products were a mix-
ture of the two isomers, partial-cone (2a) and 1,3-alternate
(3a), and the ratio of these two isomers is about 1:1 by TLC.
Interestingly, if the reaction was carried out at 50 °C for 1 h
using Ac2O as solvent in the presence of Bi(OTf)3, the main
product was 2a. Unexpectedly, the proportion of product 2a
gradually decreased when the reaction time was prolonged to
2 h. On the contrary, 3a was the unique product if CHCl3 was
used as solvent at refluxing for 1h in the presence of Bi(OTf)3.
Hence, the isomer that was formed could be controlled by
using different conditions (Scheme 2). Under other reaction
conditions, the products that were obtained were mixtures of
tetraacetates with low selectivity.
With these data in hand, tetrahydroxycalix[4]arene 1b was
chosen to investigate the stereoselectivity of this novel method.
The product are tetra-acetates that exist in the 1,3-alternate and
partial cone conformation (Table 2). It is shown that the dis-
tribution among these conformers is dependent on a variety of
factors including temperature and solvent. It can be concluded
revealed by TLC, since their Rf value was different. The H
NMR spectrum for each isomer is distinctive. It contains a
singlet resonance for the ArCH2Ar methylene hydrogens of
the 1,3-alternate isomer (Fig. 1), and several doublets for the
methylene hydrogens of the partial cone isomer. The 1H NMR
spectra of each product was identified from authentic samples
in the literature.
We also tried to synthesise other O-acetyl calix[n]arenes
(n = 6, 8) using Bi(OTf)3 as catalyst (Table 3). This showed
that the method could be used for different calix[n]arenes with
high yield. The traditional method to synthesise these product
3c–f used CH2Cl2 as a solvent and excess AlCl3 and acetyl
chloride under reflux for 1–2 h to afford the products. The
yield was about 30–50%. The 1H NMR spectrum of 3c and 3d
revealed their 1,3,5-alternate conformation whilst 3e and 3f
were 1,3,5,7-alternate conformations (Fig. 2) which were the
same as the literature.7,14
In summary, the present procedure describes an efficient
selective synthesis of acetoxy-calix[n]arenes isomers catalysed
by Bi(OTf)3. We believe that this procedure would provide a
better and more practical alternative to the existing procedures
for the preparation of derivatives of calix[n]arenes.
Table 2 Effect of temperature and solvents on the conforma-
tion distribution in the acetylation of calix[4]arene
Experimental
p-tert-Butyl-calix[n]arene and de-tert-butyl-calix[n]arenes were pre-
pared according to the literature.3,8 M(OTf)n was prepared from M2On
and triflic acid. Melting points were measured on a Büchi B-540
Entry
R
Solvents
Temp. /oC
Yield /%
2
3
1
capillary melting point apparatus. H NMR and 13C NMR spectra
1
2
3
4
5
6
t-Bu
t-Bu
t-Bu
H
H
H
Ac2O
50
72
33
8
45
65
16
40
70
were recorded on a Varian 400 MHz or Bruker Avance III (500 MHz)
instrument using CDCl3 as the solvent, and chemical shifts were
expressed in parts per million (ppm) using TMS as an internal
standard. Mass spectra were measured with a Trace Finnigan DSQ.
All spectroscpic data for the products were identical to authentic
samples.
CH2Cl2
CHCl3
Ac2O
Reflux
Reflux
50
Trace
64
CH2Cl2
CHCl3
Reflux
Reflux
42
Trace
Fig. 2 H NMR difference of protons on methene.

252 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 3
CHCl3 and Bi(OTf)3 0.011 g (0.016 mmol) and heated under reflux
Table 3 The preparation of O-acetoxy-calix[n]arene
for 1 h. It was cooled to room temperature, poured into 50 mL water,
and the organic layer was dried with anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and the product was
recrystallised from MeOH–CHCl3 to give 0.33 g (70%) 1,3-alt con-
former 3b. colourless needle. m.p. > 400 °C (lit.6 m.p. 405–406 °C);
1H NMR(CDCl3) δ 1.55 (s, 12H), 3.76 (s, 8H), 7.07 (s, 12H); 13C
NMR (CDCl3) δ 20.3, 37.5, 125.4, 129.0, 133.1, 148.2, 167.9; MS
(ESI): m/z = 591.7 (M+)
Entry
R
n
Solvent
Product
Yield a/%
1
2
3
4
t-Bu
H
t-Bu
H
6
6
8
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3c
3d
3e
3f
84
71
82
72
a Isolated yield based on 1c–f.
37,38,39,40,41,42-hexaacetoxy-5,11,17,23,29,35-hexa-tert-butylcalix
[6]arene (3c): A sample of 0.97 g (1 mmol) 1c was treated with
Ac2O 1.22 g (12 mmol) and 20 mL CH2Cl2 and Bi(OTf)3 0.013 g
(0.02 mmol), and heated under reflux for 1h. The mixture was cooled
to room temperature, poured into ice water, and the organic layer was
dried with anhydrous sodium sulfate. The solvent was evaporated and
the product recrystallised from MeOH–CHCl3 to give 3c 1.02 g (84%)
as a white solid; m.p. 334.3–335.3 °C (lit7 > 280 °C); 1H NMR(CDCl3)
δ 1.17 (s, 54H), 1.89 (s, 18H), 3.62 (s, 12H), 6.95 (s, 12H); 13C NMR
(CDCl3) δ 20.2, 31.2, 34.3, 126.0, 131.2, 145.1, 148.3, 168.6; MS
(ESI): m/z = 1224 (M+)
37,38,39,40,41,42-hexaacetoxy-calix[6]arene (3d):A 0.63 g (1 mmol)
sample 1d was treated with Ac2O 1.22g (12 mmol) and 20 mL CH2Cl2
and Bi(OTf)3 0.013 g (0.02 mmol) and heated under reflux for 2 h.
It was cooled to room temperature and poured into ice water. The
organic layer was dried with anhydrous sodium sulfate and the solvent
was evaporated. Recrystallisation of the product from MeOH–CHCl3
gave 0.63 g (71%) 3d as a white solid; m.p. 335.0–335.6 °C (lit.8
335–336 °C); 1H NMR (CDCl3) δ 1.90 (s, 18H), 3.67 (s, 12H), 6.92–
7.25 (m, 18H); 13C NMR (CDCl3) δ 20.5, 31.6, 126.4, 129.3, 132.4,
147.7, 169.0; MS (ESI): m/z =888.2 (M+)
49,50,51,52,53,54,55,56-octaacetoxy-5,11,17,23,29,35,41,47-octa-tert-
butylcalix[8]aren (3e): A 1.29 g (1 mmol) sample 1e was treated
with Ac2O 1.62 g (16 mmol) and 20 mL CH2Cl2 and Bi(OTf)3 0.013 g
(0.02 mmol), and heated under reflux for 1 h. It was cooled to room
temperature, poured into ice water and the organic layer was dried
over anhydrous sodium sulfate. The solvent was evaporated. Recryst-
allisation from MeOH–CHCl3 gave 1.24 g (82%) 3e as a white solid;
m.p. 353.8–354.6 °C (lit.7 > 280 °C); 1H NMR(CDCl3) δ 1.17 (s,
72H), 1.89 (s, 24H), 3.63 (s, 16H), 6.95 (s, 16H); 13C NMR (CDCl3)
δ 20.2, 31.2, 34.3, 126.1, 131.2, 145.1, 148.3, 168.6; MS (ESI):
m/z = 1632.5 (M+)
25,26,27,28-Tetraacetoxy-5,11,17,23-tetra-tert-butylcalix[4]arene
(2a): A 0.5 g (0.8 mmol) sample of 1a was dissolved in Ac2O (6 mL),
treated with Bi(OTf)3 0.011 g (0.016 mmol) and heated at 50 °C for
1 h. The solvent was evaporated under reduced pressure, the remain-
der washed with methanol, filtered and dried to give a white solid.
This was separated by silica gel column chromatography to give
0.45 g (72%) the paco-conformer 2a. white solid; m.p. 324.5–
1
326.1 °C (lit.6 m.p. 320 °C); H NMR(CDCl3) δ 1.09 (s, 18H), 1.36
(s, 9H), 1.40 (s, 9H), 1.90 (s, 3H), 1.99 (s, 3H), 2.32 (s, 6H), 3.24
(d, 2H, J = 13.6 Hz), 3.51 (d, 2H, J = 13.6 Hz), 3.56 (d, 2H, J = 15.2
Hz), 3.63 (d, 2H, J = 15.2 Hz), 6.83 (s, 4H), 7.23(s, 4H); 13C NMR
(CDCl3) δ 21.5, 22.2, 22.6, 31.4, 31.6, 32.0, 34.3, 34.7, 34.8, 38.3,
125.7, 125.9, 127.0, 127.4, 131.3, 132.1, 133.4, 134.2, 144.3, 144.9,
147.3, 147.5; MS (ESI): m/z = 816.7 (M+)
25,26,27,28-Tetraacetoxy-5,11,17,23-tetra-tert-butylcalix[4]arene
(3a): A mixture of 0.5 g (0.8 mmol)1a was treated with Ac2O 0.65 g
(6.4 mmol)and 8 mL CHCl3 and Bi(OTf)3 0.011g (0.016 mmol). It
was heated under reflux for 1 h, cooled to room temperature and
poured into 50 mL water. The organic layer was dried with anhydrous
sodium sulfate. The solvent was evaporated under reduced pressure
and the product was recrystallised from MeOH–CHCl3 to give 0.4 g
(65%) the 1,3-alt conformer 3a as a white solid; m.p. 382.6–384.0 °C
(lit.6 m.p. > 300 °C); 1H NMR (CDCl3) δ 1.29 (s, 36H), 1.48 (s, 12H),
3.74 (s, 8H), 7.04 (s, 8H); 13C NMR (CDCl3) δ 20.3, 31.2, 34.0, 37.8,
125.5, 132.0, 145.6, 147.1, 167.7; MS (ESI): m/z =816.7 (M+)
25,26,27,28-Tetraacetoxy-calix[4]arene (2b): A 0.34 g (0.8 mmol)
sample of 1b was dissolved in Ac2O (6 mL), treated with Bi(OTf)3
0.011 g (0.016 mmol) and heated at 50 °C for 1 h. The solvent was
evaporated and the remainder was washed with methanol, filtered and
dried to give a white solid, which was separated by silica gel column
chromatography to get 0.30 g (64%) paco-conformer 2b as colourless
plates; m.p. > 400 °C (lit.6 m.p. 402–403 °C); 1H NMR (CDCl3) δ 1.79
(s, 3H), 2.07 (s, 3H), 2.37 (s, 6H), 3.29 (d, 2H, J =13.6 Hz ), 3.57 (d,
2H, J =13.6 Hz), 3.65 (d, 2H, J =14.8 Hz), 3.70 (d, 2H, J = 14.8 Hz),
6.74–6.93 (m, 6H), 7.16–7.24 (m, 2H), 7.26–7.29 (m, 4H); 13C NMR
(CDCl3) δ 21.0, 21.4, 21.5, 30.7, 37.3, 124.7, 125.3, 126.1, 129.0,
129.4, 129.5, 130.1, 131.4, 132.5, 134.0, 134.8, 145.9, 147.6, 149.2,
168.3, 168.8, 170.2; MS (ESI): m/z =591.7 (M+)
49,50,51,52,53,54,55,56-octaacetoxy-calix[8]arene (3f): A 0.84 g
(1 mmol) sample 1f was treated with Ac2O 1.62 g (16 mmol) and
20 mL CH2Cl2 and Bi(OTf)3 0.013 g (0.02 mmol) and heated under
reflux for 2 h. It was cooled to room temperature, poured into ice
water and the organic layer was dried with anhydrous sodium sulfate.
The solvent was evaporated. Recrystallisation from MeOH–CHCl3
gave 1.17 g (72%) 3f as a white solid; m.p. 327–328 °C (lit8. m.p.
1
327–330 °C) H NMR(CDCl3) δ 1.99 (s, 24H), 3.66 (s, 16H), 6.92–
7.04 (m, 24H). 13C NMR (CDCl3) δ 20.5, 31.6, 126.4, 129.3, 132.4,
147.7, 169.0; MS (ESI): m/z = 1184.4 (M+)
25,26,27,28-Tetraacetoxy-calix[4]arene (3b): A mixture of 0.34 g
(0.8 mmol) 1b was treated with Ac2O 0.65 g (6.4 mmol) and 8 mL

JOURNAL OF CHEMICAL RESEARCH 2010 253
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We are grateful to the National Natural Science Foundation of
China (20876147), Zhejiang Natural Science Foundation
(Y4090346), and the Opening Foundation of Zhejing Provin-
cial Top Key Pharmaceutical Discipline for financial support.
5
6
7
Received 3 March 2010; accepted 14 April 2010
Paper 101032 doi: 10.3184/030823410X12731611998876
Published online: 8 June 2010
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