An efficient synthetic approach to substituted trisphenols (phloroglucide analogues) using tungstosilicic acid in water

Article abstract of DOI:10.1055/s-0033-1340681

Tungstosilicic acid was found to be an efficient catalyst for the synthesis of trisphenols using the reaction of 2,6-bis(hydroxymethyl)phenols with phenols in an aqueous medium. The catalytic reactivity of tungstosilicic acid in boiling water was examined with a series of substrates, demonstrating that this catalyst is reactive in the presence of a variety of functionalities. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340681

PAPER
▌887
paper
An Efficient Synthetic Approach to Substituted Trisphenols (Phloroglucide
Analogues) Using Tungstosilicic Acid in Water
Synthesis of Substituted Trisphenols in Water
Reza Fareghi-Alamdari,*a Ali Khalafi-Nezhad,b Negar Zekria
a
Faculty of Chemistry & Chemical Engineering, Malek-Ashtar University of Technology, Tehran, Iran
Fax +98(21)22970195; E-mail: reza_fareghi@yahoo.com
b
College of Science, Department of Chemistry, Shiraz University, Shiraz, Iran
Received: 17.11.2013; Accepted after revision: 08.01.2014
OH
R2
OH
OH
R2
X
OH
X
Abstract: Tungstosilicic acid was found to be an efficient catalyst
for the synthesis of trisphenols using the reaction of 2,6-bis(hy-
droxymethyl)phenols with phenols in an aqueous medium. The cat-
alytic reactivity of tungstosilicic acid in boiling water was examined
with a series of substrates, demonstrating that this catalyst is reac-
tive in the presence of a variety of functionalities.
+
‘3+1’
R1
R3
BMP
TP
X = Cl, Br, OH
OH
Key words: tungstosilicic acid, trisphenols, phenols, 2,6-bis(hy-
droxymethyl)phenols, synthesis
OH
R
HO
OH
R
There are many natural products, pharmaceuticals, cata-
lysts and advanced materials with phenolic structural
units.1 The presence of hydroxy groups in the structure of
these materials results in special activity.2 Some important
and biologically active phenol-based compounds have
been isolated from nature.3 Also, a large number of com-
plex molecules have been synthesized in a single or mul-
tistep process by the use of phenols as reagents in organic
reactions.4 One of the most important classes of phenolic
compounds is comprised of polyhydroxy aromatic (PHA)
compounds. Members of this category of materials show
versatile biological activities and have been used as drugs
in the treatment of many diseases.5 In addition to being
potent pharmaceuticals in their own right, they play a ver-
satile role in organic synthesis, especially for the prepara-
tion of calixarenes and macrocyclic crown ethers.6
R
R
calix[4]arenes
OH
OH
X
OH
OH
X
‘2+2’
+
R1
R1
R2
R2
BP
BP
X = Cl, Br, OH
Scheme 1 The ‘3+1’ and ‘2+2’ convergent stepwise synthesis of ca-
lix[4]arenes
The choice between the ‘3+1’ and ‘2+2’ procedures often
depends on the relative ease of construction of the compo-
nent parts; however, the diversity of the obtained ca-
lix[4]arenes via method ‘3+1’ is greater than that via
method ‘2+2’. For example, employment of a trisphenol
which carries two different substituents R1 and R2 on the
structure leads to a calix[4]arene with three differently
substituted phenyl rings.10
Calixarenes have seen widespread use as receptors for cat-
ions, anions and neutral molecules, and can be used as
sensitive sensors for the detection of special molecules.7
Owing to the wide applications and significance of calix-
arenes, there is considerable interest in the synthesis of
these compounds.8 It is noteworthy that in most of the re-
ported methods for the multistep synthesis of calixarenes,
PHA compounds are the main starting material.
On the other hand, in procedure ‘3+1’ the key step is the
synthesis of the starting trisphenols, and there are few
methods for the preparation of these compounds. Al-
though each of the methods has its benefits, they often
suffer from one or more disadvantages. Low yield, the use
of only reactive substrates, the production of analogues
containing three similar phenolic rings, the use of a large
excess of phenolic compounds, tedious workup processes,
oxidation of the phenolic hydroxy groups, alkyl isomeri-
zation and hazardous reaction conditions are the most im-
portant deficiencies associated with these methods.5f,g,11–14
The convergent stepwise synthesis (fragment condensa-
tion procedure) of calixarenes has been extensively stud-
ied by Böhmer and co-workers, with two different
strategies based on the use of PHA compounds in ‘3+1’
and ‘2+2’ procedures in which trisphenols (TP) and bis-
phenols (BP) are the main starting materials (Scheme 1).9
Owing to the importance of the described compounds, and
in continuation of our previous studies on the preparation
of polyhydroxy aromatic compounds,15 herein, we present
tungstosilicic acid (TSA) as a novel catalyst for the prep-
SYNTHESIS 2014, 46, 0887–0892
Advanced online publication: 11.02.2014
DOI: 10.1055/s-0033-1340681; Art ID: SS-2013-N0484-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

888
R. Fareghi-Alamdari et al.
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aration of trisphenols from 2,6-bis(hydroxymethyl)phe- Keggin-type heteropolyacids, were tested; no significant
nols [2,6-bis(methylol)phenols, BMP] and various improvement in the reaction yield was observed (Table 1,
substituted phenols in an aqueous medium.
entries 6 and 7). Interestingly, TSA showed a good reac-
tivity and was the best catalyst tested. In the presence of 4
mol% of TSA, compound 3a was isolated in 86% yield af-
ter only 5 hours in water as a ‘green’ solvent (Table 1, en-
try 8). The advantages in using heteropolyacid catalysts
are as follows: high catalytic performance, strong acidity,
recycling capability, selectivity to a particular reaction
product by selective stabilization of the reaction interme-
diate, safety, lower waste, and ease of separation.20 Per-
forming the reaction in the presence of ZnCl2, TiO2 or
We first synthesized BMP 1a–d based on literature proce-
dures.16 Then, the reaction between 4-chloro-2,6-bis(hy-
droxymethyl)phenol (1c) and 4-chlorophenol (2a) was
chosen as a model to establish optimized conditions for
the preparation of 4-chloro-2,6-bis(5-chloro-2-hydroxy-
benzyl)phenol (3a). The results of the optimization study
are summarized in Table 1.
When the reaction was carried out in the absence of cata-
lyst, no product was observed, even after 24 hours (Table
1, entry 1). To obtain the desired product 3a, we tested
various Brønsted and Lewis acids in the model reaction
(Table 1, entries 2–12). The use of silica sulfuric acid
(SSA)13 in water solvent led to none of the desired prod-
uct, even after 12 hours, while this catalyst showed good
reactivity in 1,4-dioxane solvent (Table 1, entries 2 and 3).
Aluminum methanesulfonic acid (AMA)17 was the next
catalyst tested for this reaction: a trace amount of product
was observed after 12 hours in water, and 35% yield of 3a
was obtained in methanol solvent (Table 1, entries 4 and
5).
Table 2 Effect of Temperature on the Reaction of BMP 1c with
4-Chlorophenol (2a) in the Presence of TSA Catalyst in Watera
Entry
Temp (°C)
Time (h)
Yieldb (%)
1
2
3
4
r.t.
24
24
12
5
trace
23
50
80
61
reflux
86
a Reaction conditions: 1c (1 mmol), 2a (3 mmol), TSA (0.04 g), H2O
Then, tungstophosphoric acid (TPA)18 and molybdato-
(5 mL).
phosphoric acid (MPA),19 as two important members of
b Isolated yield.
Table 1 Optimization of the Reaction between BMP 1c and 4-Chlorophenol (2a)a
OH
OH
OH
Cl
OH
OH
HO
OH
+
2
Cl
Cl
Cl
Cl
1c
2a
3a
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
1
2
–
H2O
24
12
2
0
SSA
SSA
AMA
AMA
TPA
MPA
TSA
H2O
0
3
1,4-dioxane
H2O
78
4
12
5
trace
35
5
MeOH
H2O
6
5
51
7
H2O
5
39
8
H2O
5
86
c
9
ZnCl2
H2O
12
12
12
12
0
c
10
11
12
TiO2
H2O
trace
0
LiClc
H2O
PTSAd
H2O
trace
a Reaction conditions: 1c (1 mmol), 2a (3 mmol), catalyst (0.04 g), solvent (5 mL), reflux.
b Isolated yield.
c 20 mol% of catalyst was used.
d 50 mol% of catalyst was used.
Synthesis 2014, 46, 887–892
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Substituted Trisphenols in Water
889
yields. The wide scope capability of this protocol was
highlighted by the application of both phenols with elec-
tron-withdrawing groups and phenols with electron-
donating groups under the same reaction conditions. In all
cases, the reactions were accomplished in relatively short
reaction times (see Table 5). The functional group com-
patibility of this reaction was highlighted by the use of 4-
allyl-2-methoxyphenol as an acid-sensitive substrate (Ta-
ble 5, entries 14 and 15).
Table 3 Optimization of the TSA Catalyst Loading in the Reaction
of BMP 1c with 4-Chlorophenol (2a) in Watera
Entry
Amount of catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
4 mol% H+
2 mol% H+
3 mol% H+
5 mol% H+
6 mol% H+
5
12
12
5
86
71
78
89
85
In general, the synthesis of trisphenols using TSA as a cat-
alyst in an aqueous medium has some advantages, includ-
ing the following: 1) the reaction is carried out in water as
a ‘green’ solvent; 2) this protocol avoids the use of corro-
sive and toxic acidic catalysts; 3) a catalytic amount of
TSA and a minimum amount of phenol are required.
5
a Reaction conditions: 1c (1 mmol), 2a (3 mmol), TSA, H2O (5 mL),
reflux.
b Isolated yield.
In summary, trisphenols were synthesized using tungsto-
silicic acid as a catalyst under mild conditions. The tungs-
tosilicic acid catalyst efficiently promoted the reaction
between phenols and 2,6-bis(hydroxymethyl)phenols in
water to produce the target products 3a–r in excellent iso-
lated yields.
Table 4 Effect of the Amount of 4-Chlorophenol (2a) in the Model
Reaction with BMP 1ca
Entry
Ratio 2a/1c
Time (h)
Yieldb (%)
1
2
3
4
3:1
5
5
89
86
78
84
4:1
Chemicals were purchased from Fluka, Merck and Aldrich Chemi-
cal Companies, and were used without further purification. Com-
pounds 1a–d were prepared according to previously reported
procedures.16 The known products were characterized by compari-
son of their spectroscopic and physical data with literature data. 1H
and 13C NMR spectra were recorded in DMSO-d6 solution with
TMS as an internal standard on a Bruker Avance 250 MHz spec-
trometer. Chemical shifts are given in the δ scale in parts per million
(ppm) and the couplings are assigned as singlet (s), doublet (d), trip-
let (t) and multiplet (m). FT-IR spectroscopy (Shimadzu FT-IR
8300 spectrophotometer) was employed for compound character-
ization. Melting points were determined in open capillary tubes in a
Barnstead Electrothermal 9100 BZ circulating oil melting point ap-
paratus. Reaction monitoring was accomplished by TLC on silica
gel Polygram SILG/UV254 plates.
2:1
12
12
2.5:1
a Reaction conditions: 1c, 2a, TSA (0.05 g), H2O (5 mL), reflux.
b Isolated yield.
LiCl as Lewis acid in water resulted in the production of
3a in trace amounts (Table 1, entries 9–11). p-Toluenesul-
fonic acid (PTSA) showed no reactivity for this reaction
in water (Table 1, entry 12).
The effect of temperature on the progress of the model re-
action was investigated next, and the results are summa-
rized in Table 2; the best yield was obtained under reflux
conditions (entry 4).
Substituted 2,6-Bis(2-hydroxybenzyl)phenols 3;
General Procedure
Into a conical flask containing a 2,6-bis(hydroxymethyl)phenol 1a–
d (1 mmol), a substituted phenol (3 mmol) and H2O (5 mL), was
added a catalytic amount of TSA (0.14 g, 5 mol%), and the reaction
mixture was refluxed. The progress of the reaction was monitored
by TLC. After completion of the reaction (see Table 5 for reaction
time), the mixture was cooled to r.t. and then extracted with EtOAc
(2 × 20 mL). The combined organic extract was dried over Na2SO4,
filtered and concentrated, and the product was purified by column
chromatography (hexane–EtOAc).
In optimization studies of the TSA catalyst loading, it was
established that 5 mol% of catalyst is sufficient to obtain
maximum product in a relatively short reaction time (Ta-
ble 3).
To determine the best stoichiometric ratio of phenol to
BMP, we performed the model reaction with 1c in the
presence of different amounts of 4-chlorophenol (2a) (Ta-
ble 4); the best yield was obtained with a ratio of 3 mmol
of phenol per 1 mmol of BMP (entry 1).
4-Chloro-2,6-bis(5-chloro-2-hydroxybenzyl)phenol (3a)12
Yield: 0.36 g (89%); yellow solid; mp 233–235 °C.
IR (KBr): 3150, 3010, 2980, 1610, 1220 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 3.82 (s, 4 H), 6.67–7.09 (m, 8
H), 8.82 (br s, 1 H), 9.82 (br s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 29.6, 116.4, 122.4, 122.8,
126.9, 127.2, 128.4, 129.4, 129.5, 151.4, 153.9.
Thus, under the optimized reaction conditions (refluxing
water, 5 mol% catalyst loading, ratio phenol/BMP 3:1), a
series of trisphenols 3b–r were synthesized (Table 5).
It is clear from Table 5 that the TSA catalyst is effective
for the synthesis of trisphenols using the reaction of phe-
nols with BMP. Although the catalytic activity of TSA is
dependent on the type of phenol, all of the phenols were
converted into the corresponding products in excellent
Anal. Calcd for C20H15Cl3O3: C, 58.63; H, 3.69. Found: C, 58.61; H,
3.70.
4-Chloro-2,6-bis(2-hydroxy-5-methylbenzyl)phenol (3b)12
Yield: 0.30 g (82%); white solid; mp 137–139 °C.
IR (KBr): 3208, 3018, 2876, 1605, 1448, 810 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 887–892

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R. Fareghi-Alamdari et al.
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Table 5 Synthesis of Trisphenols 3 by the Reaction of Phenols with 2,6-Bis(hydroxymethyl)phenols Using TSA in Refluxing Water
OH
Y
OH
OH
Y
OH
OH
Z
Z
Z
TSA (5 mol%)
HO
OH
+
2
H2O (5 mL)
reflux
X
Y
X
3a–m
1 mmol
3 mmol
1a: X = Me, 1b: X = F
1c: X = Cl, 1d: X = Br
Entry
X
Y
Z
Time (h)
Product
Yielda (%)
1
Cl
Cl
Cl
Br
Cl
Br
F
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
5
4
5
5
6
6
5
5
3
6
6
5
5
6
6
8
8
5
3a
3b
3c
3d
3e
3f
89
82
81
81
85
84
89
87
86
80
82
83
80
81
80
79
79
85
2
Me
3
F
4
Br
5
Br
6
Cl
7
F
3g
3h
3i
8
Me
Cl
Cl
Cl
Br
Me
Cl
Br
F
Cl
9
OH
10
NO2
3j
11
Ph
3k
3l
12
F
13
Me
3m
3n
3o
3p
3q
3r
14
CH2CH=CH2
OMe
OMe
Ac
15
CH2CH=CH2
16
F
17
Cl
Cl
F
Ac
18
Me
t-Bu
a Isolated yields.
1H NMR (250 MHz, DMSO-d6): δ = 2.13 (s, 6 H), 3.77 (s, 4 H),
6.68–6.83 (m, 8 H), 8.69 (br s, 1 H), 9.34 (br s, 2 H).
4-Bromo-2,6-bis(5-bromo-2-hydroxybenzyl)phenol (3d)12
Yield: 0.44 g (81%); yellow solid; mp 237–238 °C.
IR (KBr): 3200, 3090, 2950, 1600, 1250 cm–1.
13C NMR (62.5 MHz, DMSO-d6): δ = 20.1, 29.6, 114.8, 122.6,
1H NMR (250 MHz, DMSO-d6): δ = 3.81 (s, 4 H), 6.76–7.20 (m, 8
125.6, 126.7, 127.5, 127.6, 130.1, 130.9, 151.1, 152.4.
H), 8.8 (s, 1 H), 9.89 (s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 29.4, 110.0, 110.7, 117.0,
Anal. Calcd for C22H21ClO3: C, 71.64; H, 5.74. Found: C, 71.73; H,
5.81.
128.9, 129.8, 129.9, 130.0, 132.3, 151.8, 154.3.
4-Chloro-2,6-bis(5-fluoro-2-hydroxybenzyl)phenol (3c)13
Yield: 0.32 (81%); white solid; mp 223–224 °C.
Anal. Calcd for C20H15Br3O3: C, 44.23; H, 2.78. Found: C, 44.23;
H, 2.83.
IR (KBr): 3190, 1600, 1495, 1445, 1235, 1190 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 3.80 (s, 4 H), 6.77–6.89 (m, 8
H), 8.75 (s, 1 H), 9.57 (s, 2 H).
2,6-Bis(5-bromo-2-hydroxybenzyl)-4-chlorophenol (3e)13
Yield: 0.42 g (85%); white solid; mp 251–253 °C.
IR (KBr): 3150, 3020, 2990, 1600, 1220 cm–1.
13C NMR (62.5 MHz, DMSO-d6): δ = 29.7, 113.1, 113.4, 115.5,
1H NMR (250 MHz, DMSO-d6): δ = 3.84 (s, 4 H), 6.78–7.21 (m, 8
116.1, 122.9, 127.1, 127.6, 129.5, 151.3, 153.5, 157.2.
H), 9.68 (br s, 3 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 29.6, 110.1, 117.0, 122.9,
Anal. Calcd for C20H15ClF2O3: C, 63.75; H, 4.01. Found: C, 63.67;
H, 3.92.
127.2, 128.9, 129.4, 129.8, 132.4, 151.4, 154.3.
Synthesis 2014, 46, 887–892
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Substituted Trisphenols in Water
891
Anal. Calcd for C20H15Br2ClO3: C, 48.18; H, 3.03. Found: C, 48.27;
H, 3.09.
13C NMR (62.5 MHz, DMSO-d6): δ = 33.4, 115.7, 117.3, 125.2,
125.8, 125.9, 126.7, 128.3, 128.6, 129.7, 129.8, 130.9, 140.6, 157.2,
159.7.
4-Bromo-2,6-bis(5-chloro-2-hydroxybenzyl)phenol (3f)13
Yield: 0.38 g (84%); pale-yellow solid; mp 235–236 °C.
IR (KBr): 3150, 3050, 2950, 1600, 1220 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 3.82 (s, 4 H), 6.74–7.18 (m, 8
H), 8.8 (br s, 1 H), 9.86 (br s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 29.5, 110.7, 116.4, 122.4,
126.9, 128.3, 129.0, 129.5, 130.0, 151.9, 153.8.
Anal. Calcd for C32H25ClO3: C, 77.96; H, 5.11. Found: C, 78.11; H,
5.16.
4-Bromo-2,6-bis(5-fluoro-2-hydroxybenzyl)phenol (3l)16
Yield: 0.35 g (83%); white solid; mp 231–232 °C.
IR (KBr): 3190, 2935, 1612, 1501, 1241, 1019 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 3.81 (s, 4 H), 6.74–7.03 (m, 8
H), 9.36 (br s, 3 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 29.7, 110.6, 113.0, 113.4,
Anal. Calcd for C20H15BrCl2O3: C, 52.89; H, 3.33. Found: C, 52.95;
H, 3.36.
115.6, 116.5, 127.6, 130.0, 151.0, 151.9.
4-Fluoro-2,6-bis(5-fluoro-2-hydroxybenzyl)phenol (3g)21
Anal. Calcd for C20H15BrF2O3: C, 57.03; H, 3.59. Found: C, 57.10;
H, 3.64.
Yield: 0.32 g (89%); white solid; mp 239–240 °C.
IR (KBr): 3150, 3050, 2950, 1600, 1220 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 3.82 (s, 4 H), 6.58–6.84 (m, 8
H), 8.5 (br s, 1 H), 9.56 (br s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 15.8, 123.8, 124.0, 125.4,
2,6-Bis(2-hydroxy-5-methylbenzyl)-4-methylphenol (3m)14
Yield: 0.28 g (80%); white solid; mp 214–215.5 °C.
IR (KBr): 3440, 3291, 3001, 1580, 1430, 1345, 1231 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 2.06 (s, 3 H), 2.14 (s, 6 H),
126.6, 127.2, 128.5, 132.8, 134.2, 151.5.
3.82 (s, 4 H), 6.64–6.82 (m, 8 H), 9.25 (s, 3 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 20.2, 20.3, 29.6, 114.7,
Anal. Calcd for C20H15F3O3: C, 66.67; H, 4.20. Found: C, 66.71; H,
4.24.
126.7, 127.2, 127.3, 127.4, 127.5, 128.2, 130.6, 149.8, 152.1.
2,6-Bis(5-chloro-2-hydroxybenzyl)-4-methylphenol (3h)14
Anal. Calcd for C23H24O3: C, 79.28; H, 6.94. Found: C, 79.35; H,
6.99.
Yield: 0.34 g (87%); white solid; mp 235–236 °C.
IR (KBr): 3135, 3030, 2930, 1600, 1485, 1420, 1390 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 2.06 (s, 3 H), 3.80 (s, 4 H),
6.63–7.19 (m, 8 H), 8.32 (br s, 1 H), 9.8 (br s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 20.3, 29.6, 116.2, 122.3,
126.4, 126.7, 127.7, 128.0, 129.2, 129.5, 144.9, 153.7.
6,6′-[(5-Chloro-2-hydroxy-1,3-phenylene)bis(methylene)]bis(4-
allyl-2-methoxyphenol) (3n)13
Yield: 0.39 g (81%); pale-yellow solid; mp 55–57 °C.
IR (KBr): 3450, 3090, 2985, 2950, 1600, 1510, 1450 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 3.16 (d, J = 6.6 Hz, 4 H), 3.63
(s, 4 H), 3.72 (s, 6 H), 4.83 (dd, J = 16.5, 10.3 Hz, 4 H), 5.21 (br s,
3 H), 5.71–5.73 (m, 2 H), 6.89–7.31 (m, 6 H).
Anal. Calcd for C21H18Cl2O3: C, 64.79; H, 4.66. Found: C, 64.83; H,
4.69.
13C NMR (62.5 MHz, DMSO-d6): δ = 30.1, 40.0, 56.4, 111.3,
115.4, 117.5, 122.7, 124.4, 125.9, 128.7, 134.0, 138.8, 141.7, 143.0,
156.3.
2,2′-[(5-Chloro-2-hydroxy-1,3-phenylene)bis(methy-
lene)]bis(benzene-1,4-diol) (3i)12
Yield: 0.32 g (86%); light-brown crystals; mp 179–180 °C.
IR (KBr): 3200, 3020, 2990, 1610, 1600, 1500, 1450, 1250, 850
cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 3.89 (s, 4 H), 6.49–6.83 (m, 8
H), 8.65 (s, 2 H), 8.77 (br s, 1 H), 9.00 (br s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 29.7, 113.6, 115.5, 116.8,
Anal. Calcd for C28H29ClO5: C, 69.92; H, 6.08. Found: C, 70.01; H,
6.15.
6,6′-[(5-Bromo-2-hydroxy-1,3-phenylene)bis(methylene)]bis(4-
allyl-2-methoxyphenol) (3o)13
Yield: 0.42 g (80%); light-brown solid; mp 59–60 °C.
IR (KBr): 3450, 3087, 2982, 2953, 1659, 1516, 1432, 1198 cm–1.
122.7, 126.7, 126.8, 130.0, 147.0, 149.7, 151.2.
Anal. Calcd for C20H17ClO5: C, 64.44; H, 4.60. Found: C, 64.42; H,
4.67.
1H NMR (250 MHz, DMSO-d6): δ = 3.36 (d, J = 6.4 Hz, 4 H), 3.86
(s, 4 H), 4.39 (s, 6 H), 5.03 (dd, J = 16.8, 10.3 Hz, 4 H), 5.15 (br s,
3 H), 5.95–5.97 (m, 2 H), 6.47–7.33 (m, 6 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 29.6, 40.4, 56.5, 111.4,
115.3, 117.7, 122.7, 124.4, 125.8, 128.7, 134.5, 138.3, 141.3, 143.2,
154.4.
4-Chloro-2,6-bis(2-hydroxy-5-nitrobenzyl)phenol (3j)13
Yield: 0.34 g (80%); yellow solid; mp 221–223 °C.
IR (KBr): 3400, 3090, 2920, 1630, 1590, 1500, 1300 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 3.86 (s, 4 H), 6.87–7.06 (m, 4
H), 7.89–8.22 (m, 4 H), 8.86 (br s, 1 H), 11.15 (br s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 29.6, 114.9, 122.9, 124.0,
Anal. Calcd for C28H29BrO5: C, 64.01; H, 5.56. Found: C, 64.09; H,
5.61.
125.7, 127.6, 128.8, 129.4, 139.5, 151.6, 161.8.
1,1′-{[(5-Fluoro-2-hydroxy-1,3-phenylene)bis(methy-
lene)]bis(5-fluoro-2-hydroxy-3,1-phenylene)}bis(ethan-1-one)
(3p)
Anal. Calcd for C20H15ClN2O7: C, 55.76; H, 3.51. Found: C, 55.85;
H, 3.46.
Yield: 0.35 g (79%); light-yellow solid; mp 145–147 °C.
IR (KBr): 3460, 3085, 2980, 1600, 1450, 1211, 1095, 1005, 950 cm–1.
3,3′-[(5-Chloro-2-hydroxy-1,3-phenylene)bis(methy-
lene)]bis(1,1′-biphenyl-4-ol) (3k)13
1H NMR (250 MHz, DMSO-d6): δ = 2.64 (s, 6 H), 3.92 (s, 4 H),
6.63 (d, J = 9.2 Hz, 1 H), 6.83 (s, 1 H), 7.10–7.20 (m, 2 H), 7.67 (dd,
J = 8.6, 2.2 Hz, 2 H), 8.56 (s, 1 H), 8.89 (s, 1 H), 12.41 (s, 1 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 27.1, 29.1, 114.0, 114.7,
118.7, 123.6, 124.0, 127.5, 128.5, 130.6, 151.9, 155.7, 205.3.
Yield: 0.40 g (82%); white solid; mp 144–145 °C.
IR (KBr): 3200, 3030, 2910, 1610, 1600, 1520, 1490, 1220 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 3.87 (s, 4 H), 6.7–7.61 (m, 18
H), 8.82 (s, 1 H), 9.79 (s, 2 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 887–892

892
R. Fareghi-Alamdari et al.
PAPER
Anal. Calcd for C24H19F3O5: C, 64.86; H, 4.31. Found: C, 64.79; H,
4.26.
Prod. 2006, 69, 853. (c) Nomura, T.; Hano, Y. Nat. Prod.
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1,1′-{[(5-Chloro-2-hydroxy-1,3-phenylene)bis(methy-
lene)]bis(5-fluoro-2-hydroxy-3,1-phenylene)}bis(ethan-1-one)
(3q)
(4) (a) Money, T. Chem. Rev. 1970, 70, 553. (b) Kametani, T.;
Fukumoto, K.; Yagi, H.; Satoh, F. Chem. Commun. 1967,
878.
Yield: 0.37 g (79%); pale-yellow solid; mp 149–151 °C.
(5) (a) Widén, C.-J.; Fraser-Jenkins, C. R.; Lounasmaa, M.;
Euw, J.v.; Reichstein, T. Helv. Chim. Acta 1973, 56, 831.
(b) Appendino, G.; Ottino, M.; Marquez, N.; Bianchi, F.;
Giana, A.; Ballero, M.; Sterner, O.; Fiebich, B. L.; Munoz,
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172, 201. (e) Fu, G. M.; Yu, B. Y.; Zhu, D. N. J. Asian Nat.
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A. A. Helv. Chim. Acta 1981, 64, 599. (g) Moshfegh, A. A.;
Mazandarani, B.; Nahid, A.; Hakimelahi, G. H. Helv. Chim.
Acta 1982, 65, 1229.
IR (KBr): 3390, 3061, 2985, 1593, 1448, 1201, 1090, 1025, 890
cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 2.64 (s, 6 H), 3.91 (s, 4 H),
6.83 (s, 2 H), 7.14–7.19 (m, 2 H), 7.64–7.69 (m, 2 H), 8.89 (s, 1 H),
12.41 (s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 27.1, 29.1, 114.4, 114.7,
118.7, 123.0, 123.6, 124.0, 127.5, 128.8, 130.5, 130.6, 151.7, 151.9,
155.7, 205.2, 205.3.
Anal. Calcd for C24H19ClF2O5: C, 62.55; H, 4.16. Found: C, 62.49;
H, 4.11.
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(7) Sharma, K.; Cragg, P. J. Chem. Sens. 2011, 1, 1.
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RSC Publishing: Cambridge, 2008. (b) Calixarenes; Asfari,
Z.; Böhmer, V.; Harrowfield, J.; Vicens, J.; Saadioui, M.,
Eds.; Kluwer Academic Publishers: Dordrecht, 2001.
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J. Chem. Soc., Chem. Commun. 1987, 896. (c) Böhmer, V.;
Vogt, W. Pure Appl. Chem. 1993, 65, 403. (d) Pappalardo,
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6,6′-[(5-Chloro-2-hydroxy-1,3-phenylene)bis(methylene)]bis(2-
tert-butyl-4-methylphenol) (3r)
Yield: 0.41 g (85%); white solid; mp 191–193 °C.
IR (KBr): 3552, 3510, 2995, 2915, 1445, 1170, 1090, 1020, 870 cm–1.
1H NMR (250 MHz, DMSO-d6): δ = 1.38 (s, 18 H), 2.11 (s, 6 H),
3.95 (s, 4 H), 6.61–6.97 (m, 6 H), 7.45 (s, 1 H), 8.12 (s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 20.9, 29.6, 32.2, 35.1, 126.0,
127.5, 127.8, 128.5, 131.6, 131.8, 135.0, 137.9, 147.2, 151.1.
Anal. Calcd for C30H37ClO3: C, 74.90; H, 7.75. Found: C, 74.99; H,
7.81.
Acknowledgment
We acknowledge the financial support from the Malek-Ashtar
University of Technology.
(11) Rodia, J. S. J. Org. Chem. 1961, 26, 2966.
(12) Khalafi-Nezhad, A.; Soltani Rad, M. N.; Hakimelahi, G. H.
Helv. Chim. Acta 2003, 86, 2396.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(13) Khalafi-Nezhad, A.; Parhami, A.; Bargebid, R.; Molazade,
S.; Zare, A.; Foroughi, H. Mol. Diversity 2011, 15, 373.
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Synthesis 2014, 46, 887–892
© Georg Thieme Verlag Stuttgart · New York