Synthesis and conformational studies of tetrahydroxy-[3.1.3.1]metacyclophanes and electrophilic aromatic substitution of their tetramethoxy derivatives

Article abstract of DOI:10.1039/a606358f

Base-catalysed condensation of 1,3-bis(5-tert-butyl-2-hydroxyphenyl)propane 5 with formaldehyde in xylene has been carried out to form the novel propane-bridged calixarene-type macrocyclic compound, tetrahydroxy[3.1.3.1]metacyclophane 6. The optimum yield

Full text of DOI:10.1039/a606358f

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Synthesis and conformational studies of tetrahydroxy-
[3.1.3.1]metacyclophanes and electrophilic aromatic substitution of
their tetramethoxy derivatives
Takehiko Yamato,* Yoshiyuki Saruwatari and Masashi Yasumatsu
Department of Applied Chemistry, Faculty of Science and Engineering, Saga University,
Honjo-machi 1, Saga-shi, Saga 840, Japan
Base-catalysed condensation of 1,3-bis(5-tert-butyl-2-hydroxyphenyl)propane 5 with formaldehyde in
xylene has been carried out to form the novel propane-bridged calixarene-type macrocyclic compound,
tetrahydroxy[3.1.3.1]metacyclophane 6. The optimum yield (90%) of 6 is obtained with N aOH as the
base, the use of other alkali-metal hydroxides giving lower yields. AlCl3–M eN O2-catalysed trans-tert-
butylation of 6 in benzene affords 7 in 80% yield. Intramolecular hydrogen bonding has been observed in
the tetraols 6 and 7 as comparable to calix[4]arene.
M ethylation of 7 with M eI affords the tetramethoxy derivative 11a. The stability of multi-membered
carbon skeletons permits the interconversion of functional groups at the lower and upper rims without
special regard to ring-opening side-reactions on the upper rim. For example, the introduction of Br,
formyl and acetyl substituents has been achieved by electrophilic aromatic substitution of the
tetramethoxy derivative 11a. The 1H N M R spectral behaviour of these macrocyclic metacyclophanes is
also discussed.
OMe
OMe
OMe
Introduction
Br
The calixarenes [1n]MCPs (MCP = metacyclophane), prepared
by base-catalysed condensation of para-substituted phenols
with formaldehyde, are attractive matrices, their phenolic
hydroxy groups being ordered in well-shaped cyclic arrays as a
result of strong intramolecular hydrogen bonding,1,2 which may
be functionalized into novel guest inclusion blocks.3,4 Because
of our interest in calixarene-type host compounds having dif-
ferent cavities and several binding units, we have developed
various functionalized host compounds with different bridged
chains. It is surprising that there have been so few reports of the
preparation of calixarenes containing bridges other than
methylene groups and characterization of their hydrogen bond-
ing.5 We have recently demonstrated for the first time the con-
venient synthesis of the ethylene-bridged calixarene-analogous
MCPs such as [(2.1)n]MCPs by base-catalysed condensation of
1,2-bis(5-tert-butyl-2-hydroxyphenyl)ethane with formaldehyde
in refluxing xylene and have disclosed their unique properties.5e
However, the desired tetrahydroxy[(2.1)2]MCP was not
obtained by this method. Instead, a mixture of higher ana-
logues, trimer and tetramers {e.g. hexahydroxy[(2.1)3]MCP and
octahydroxy[(2.1)4]MCP} were obtained in good yield. This
seems to be a result of tetrahydroxy[(2.1)2]MCP having a much
more strained structure than the higher analogues containing
a larger ring. This strategy was thought likely to be useful for
the preparation of tetrahydroxy[(3.1)2]MCP, since the strain
associated with the tetrahydroxy[(2.1)2]MCP system was
expected to be less because of the presence of two methylene
bridges. In this paper, we describe the convenient preparation
and conformational properties of propane-bridged calixarene-
type macrocyclic MCPs, [3.1.3.1]MCPs, synthesized by a base-
catalysed condensation of 1,3-bis(5-tert-butyl-2-hydroxy-
phenyl)propane 5 with formaldehyde.
i
ii
(90%)
(70%)
1
2
3
(88%)
iii, iv
OH
OH
OMe
OMe
v
(90%)
5
4
Scheme 1 Reagents and conditions: i, 2,6-di-tert-butyl-p-cresol, AlCl3–
MeNO2; ii, Br2, CCl4; iii, Mg, THF; iv, Br(CH2)3Br, CuBr, HMPA,
reflux for 17 h; v, BBr3, CH2Cl2, room temp. for 24 h
Condensation of 5 with formaldehyde in xylene under basic
conditions the same as the procedure that Gutsche used for the
preparation of calix[6]arene2 afforded 6,13,22,29-tetra-tert-
butyl-9,16,25,32-tetrahydroxy[3.1.3.1]MCP 6. The optimum
yield (90%) of 6 was obtained with NaOH as the base; the use
of other alkali-metal hydroxides, cf. LiOH, KOH, CsOH and
RbOH, giving lower yields: 10, 36, 26 and 10%, respectively.
These results suggest that Naϩ serves as a template alkali metal
for the formation of [3.1.3.1]MCP 6 (Scheme 2).
The AlCl3–MeNO2-catalysed trans-tert-butylation of 6 in
benzene at 20 ЊC for 24 h afforded the desired de-tert-butylated
product 7 (30%) along with recovery of the starting compound
and the formation of incompletely de-tert-butylated products.
The prolonged reaction time of 48 h led to complete trans-tert-
butylation to afford 7 (80%). However, use of toluene as an
acceptor for the tert-butyl group failed, only ring-cleavage as a
result of the transbenzylation occurring. Thus, ring-cleavage as
a result of transbenzylation rather than trans-tert-butylation
was favourable under the conditions used (Table 2).
Results and discussion
The starting compound, 1,3-bis(5-tert-butyl-2-hydroxyphenyl)-
propane 5 was prepared in 4 steps (Scheme 1) from anisole 1 by
using the tert-butyl group as a positional protective group on
the aromatic ring.6,7
J. Chem. Soc., Perkin Trans. 1, 1997
1725

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Table
3
Selected 1H NMR and IR spectral data for p-tert-
butylcalix[4]arene 9, p-tert-butyltetrahydroxy[2.1.2.1]MCP 10 and
6
29
tetrahydroxy[3.1.3.1]MCPs 6 and 7a
32
25
9
OH
OH
HO
HO
i
5
16
OH
OH
OH
HO
HO
HO
22
13
OHHO
6
Scheme 2 (See Table 1). Reagents and conditions: i, (HCHO)x, MOH,
xylene, reflux for 16 h.
10
9
Compds
νOH (KBr)/cmϪ1
δH (CDCl3) OH
Tc (∆Gc‡)
R
9
10
6
3160
3418
3254
3485, 3529
10.2
8.8
9.35
9.5
52 (15.7)
<Ϫ40b
0 (12.5)
0 (13.7)
OH
OH
HO
HO
i
+
6
7
Key: Tc (ЊC); ∆Gc‡ (kcal molϪ1). Tc and ∆Gc‡ were determined in
CDCl3 by using SiMe4 as reference unless indicated otherwise. b Sol-
vent: CDCl3–CS2 = 1:3.
a
8a R = H
b R = Me
7
Scheme 3 (See Table 2). Reagents and conditions: i, AlCl3–MeNO2,
ArH.
tetrahydroxy[1.1.1.1]MCP (calix[4]arene). p-tert-Butyltetra-
hydroxy[2.1.2.1]MCP 10,5a on the other hand, exhibits a higher
frequency and upfield shift (νOH = 3418 cmϪ1 and δOH = 8.8
in CDCl3) and much lower coalescence temperature value
(Tc < Ϫ40 ЊC in CDCl3–CS2 1:3) than those in tetrahydroxy-
[3.1.3.1]MCP 6 (Tc = 0 ЊC in CDCl3). It is expected to be
slightly more difficult to inhibit the rotation in tetrahydroxy-
[3.1.3.1]MCP 6 than in 10 in spite of the inner cavity of 6
being apparently larger than that of tetrahydroxy[2.1.2.1]MCP
10 due to the diarylpropane linkage. This finding is easily
rationalized by the staggered conformation of the diarylpro-
pane-like [3.3]MCPs, which adopt a syn-conformation.9 Hence
the ring of tetrahydroxy[3.1.3.1]MCP 6 is more rigid than that
of tetrahydroxy[2.1.2.1]MCP 10 because of the stronger intra-
molecular hydrogen bonding.
Table 1 Condensation of 5 with paraformaldehyde in the presence of
alkali-metal hydroxides
Run
Alkali hydroxide
Product yield (%)a 6
1
2
3
4
5
LiOH
NaOH
KOH
RbOH
CsOH
10
90
36
26
10
a
Isolated yields are shown.
Table
2
AlCl3–MeNO2-catalysed trans-tert-butylation of tetra-
hydroxy[3.1.3.1]MCP 6
In comparison with the structural characteristics of
a
AlCl3/6
(mol/mol)
Temp.
(T/ЊC)
Time
(t/h)
Products
Run
ArH
yield (%)a
calix[4]arene whose cyclophane ring is composed of a 16-
membered ring, the tetraol 6 has a cavity composed of a 20-
membered ring. Gutsche and his co-workers1a have reported
that the strong intramolecular hydrogen bond of calix[4]arene
may fix the ‘cone’ shape conformation. A conformational inver-
sion has also been observed in this system [free energy of acti-
vation for inversion ∆G‡ = 15.7 kcal molϪ1 (1 cal = 4.184 J)].8
In the 1H NMR spectrum for the macrocycle 6, signals for tert-
butyls, methylenes, aromatics and phenolic-OH are singlets at
room temperature because of rapid conformational flipping.
However, at Ϫ40 ЊC in CDCl3 the singlet signal for methylene
protons of ArCH2Ar splits into two sets of doublets (AB sys-
tem, JAB = 14 Hz) at δ 3.46 and 4.36; similarly, the benzyl
methylene protons of the propane bridge are also observed to
be split at δ 2.32 and 3.27. This behaviour is rationalized by the
conformational inversion of the macrocycle 6 in the same way
as Gutsche’s tetrahydroxy[1.1.1.1]MCPs (calix[4]arenes).8 The
1
2
3
4
5
6
Benzene
Benzene
Benzene
Benzenec
Toluene
Toluene
3.8
3.8
3.8
3.8
3.8
7.2
20
20
20
Reflux
Reflux
Reflux
1
24
48
6
1
3
0b
30c
80
60
0b
20d
Isolated yields are shown. b Starting compound 6 was recovered in
100% yield. c Recovery of 6 and formation of incompletely debutylated
products were observed. d Formation of ring-cleavage reaction products
due to the transbenzylation was observed.
a
The calixarenes show concentration-independent hydroxy
stretching bands in the 3200 cmϪ1 region of their IR spectra and
a signal at δ = 9–10 in their 1H NMR spectra, indicative of very
strong intramolecular hydrogen bonding and the cyclic nature
of calixarenes.1 The IR spectrum of the tetraol 6 shows the
absorption of the hydroxy stretching vibration around 3254
cmϪ1. The 1H NMR spectra (in CDCl3) exhibit signals for
hydroxy groups around δ = 9.35. The νOH and δOH values for
the tetraol 6 in which four hydroxy groups are close neigh-
bours, show both a slightly higher frequency and upfield shift;
this implies that the hydrogen bond is weaker than that in
But
But
But
OH
OH
HO
But
HO
(1)
H O
H O
But
O H
O H
But
But
But
the corresponding calix[4]arene 9 (νOH = 3160 cmϪ1 and δOH
10.2 in CDCl3) and calix[6]arene (νOH = 3150 cmϪ1 and δOH
=
=
temperature of coalescence is 0 ЊC and the free energy of acti-
vation for inversion is estimated to be 12.5 kcal molϪ1
(Tc = 0 ЊC, ∆ν = 243.65 Hz). The rate of conformational ring
flipping of 6 is faster than the NMR time-scale above this tem-
perature. The value of the free energy of activation for inversion
10.5 in CDCl3).8 These results strongly suggest that the intra-
molecular hydrogen bonding associated with the hydroxy
groups attached to diarylpropane units is weaker than that for
those attached to diarylmethane units in the corresponding
1726
J. Chem. Soc., Perkin Trans. 1, 1997

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is smaller than that of calix[4]arene (15.7 kcal molϪ1).8 Thus,
this indicates that the tetraol 6 is much more flexible than the
calix[4]arene. This is attributed to the increase in ring size by the
introduction of two propane-bridges in place of two methylene-
bridges in the calix[4]arene.
It was also found that below Ϫ40 ЊC, the singlet signal for
phenolic-OH at δ 9.35 splits into two sets of singlets at δ 9.15
and 10.12. This phenomenon seems to be attributed to the for-
mation of two sets of non-equivalent phenolic-OHs because the
conformational fluctuation of the cyclophane ring is frozen
below this temperature by the intramolecular hydrogen bond-
ing between the OH groups on facing benzene rings [see eqn.
(2)]. The estimated free energy for fluctuation is 10.5 kcal molϪ1
(Tc = Ϫ40 ЊC, ∆ν = 261.72 Hz).
But
But
But
But
H
H
O
O
O
O
H
H
(2)
H
O
O
H
O
H
H
O
But
But
But
But
strong hydrogen bonding
weak hydrogen bonding
From dynamic 1H NMR studies and considering the Corey–
Pauling–Koltun (CPK) model of the macrocycle 6, it is con-
cluded that below 0 ЊC the conformation of the macrocycle 6
would be expected to be in a ‘flattened 1,3-alternate form’ as a
result of calix[4]arene-like intramolecular hydrogen bonding
between the OH groups. The same results have been obtained
for the tetraol 7. However, in comparison with 6, 7 adopts a
slightly more rigid conformation. These results seem to indicate
that the bulky tert-butyl groups in 6 may weaken the intra-
molecular hydrogen bonding by creating a sterically crowded
environment in the fixed conformation.
1
Fig. 1 Partial dynamic H NMR spectra of the tetraol 6 in CDCl3–
CS2 (1:3) at 270 MHz
One of the principal reasons for an interest in calixarenes is
their potential for serving as enzyme mimics. If they are to
operate in this capacity, however, it is necessary that they should
carry functional groups of various types. Gutsche et al.
reported that the p-tert-butylcalixarenes have proved to be
excellent precursors for the introduction of functional groups
into the para-position, since the tert-butyl group is easily
removed by trans-alkylation.1,11 For example, Shinkai et al. suc-
ceeded in preparing water-soluble calixarenes by introduction
of sulfonate groups.12 Initially, they prepared the corresponding
p-nitro compound by treatment of p-sulfonatocalixarenes with
nitric acid.13 More recently, efficient direct nitration and ipso-
nitration of tert-butylcalixarenes have been reported.14 Thus,
there is substantial interest in investigating the introduction
of substituents at the para-position into tetrahydroxy[3.1.3.1]-
MCP 7 in order to prepare novel host compounds.
OMe
OMe
i
(CH2)3
6a, 7
R
R
2
11a R = H
(85%)
b R = But (96%)
Scheme 4 Reagents and conditions: i, NaH–DMF–THF, room temp.
In fact, the selective introduction of four sulfonate groups at
the para-position of the tetraol 7 by electrophilic aromatic sul-
fonation has been shown to afford the desired compound 12
without rupture of the macrocyclic ring. The stability of multi-
membered carbon skeletons was found to be an advantage. It
permits the interconversion of functional groups without ring-
opening side reactions such as those occurring with hexahomo-
trioxacalix[3]arenes and their ethereal linkages.15 The inclusion
properties of 12 for various guests will be reported in detail in
the near future.
for 1 h; ii, MeI, reflux for 3 h
On the other hand, in the spectra of the tetramethoxy
derivative 11b, which was prepared by methylation of 6 with
MeI in the presence of NaH, the protons for the tert-butyl
and methoxy groups, together with those of the methylene
bridges, appeared as singlets even below Ϫ60 ЊC. The same
phenomenon has been also observed for tetramethoxy deriva-
tive 11a derived from the tetraol 7. These findings suggest that
11 has a much more flexible structure than the macrocycles 6
and 7.
Consideration of the structures of 6 and 7 based on CPK
models suggests that the diphenylmethane moieties may have
a ‘stepped conformation’ like anti-[2.2]metacyclophane.10 The
intramolecular hydrogen bonding is apparently much shorter for
the diphenylmethane linkage than that for the diphenylpropane
linkage, although weaker hydrogen bonding is still possible.
It is concluded that the calix[4]arene-like intramolecular hydro-
gen bonds could fix the conformation of the tetrahydroxy-
[3.1.3.1]MCPs 6 and 7 in a ‘stepped-flattened 1,3-alternate
form’.
OH
OH
i, ii
(CH2)3
7
(54%)
SO3Na
SO3Na
2
12
Scheme 5 Reagents and conditions: i, H2SO4, 60 ЊC for 6 h; ii,
Ba(OH)2, Na2CO3
J. Chem. Soc., Perkin Trans. 1, 1997
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Bromination of the tetramethyl ether 11a with bromine in the
presence of iron powder proceeds smoothly, affording the
tetrabromo compound 13a (62%). In a similar fashion, TiCl4-
catalysed Friedel–Crafts reactions such as chloromethylation
with chloromethyl methyl ether, formylation with dichloro-
methyl methyl ether and acetylation with acetic anhydride yield
the corresponding para-substituted [3.1.3.1]MCPs 13b–d in
good yield. These results seem to reflect the highly regio-
selective nature of the tetramethyl ether 11a towards electro-
philic aromatic substitution.
An alternative reaction sequence for the introduction of
functional groups into the tetrahydroxy[3.1.3.1]MCPs has been
developed which involves the conversion of the tetraol 7 into
the tetraallyl ether 14. When heated in diethylaniline, 14
undergoes a four-fold para-Claisen rearrangement to afford the
p-allyl tetraol 15 (80%) as in the preparation of p-allyl-
calixarenes.16
upper rim of the tetraol 7 by direct four-fold sulfonation using
sulfonic acid. Various substituents have been introduced at the
para-positions of [3.1.3.1]MCP by direct electrophilic aromatic
substitution of the tetramethoxy derivative 11a. The p-allyl
tetraol 15 was obtained in 80% yield by a four-fold p-Claisen
rearrangement of the tetraallyl ether 14. The stability of the
multi-membered carbon skeletons was found to be an advan-
tage in that it permits the interconversion of functional groups
without ring-opening side reactions. The results consistently
suggest that the metacyclophanes 6 and 7 are rich sources of
a new type of host compounds. We are now presently testing
their behaviour in this role.
Experimental
All mps and bps are uncorrected. NMR spectra were deter-
mined at 270 MHz with a Nippon Denshi JEOL FT-270 NMR
spectrometer with SiMe4 as an internal reference: J values are
given in Hz. IR spectra were measured for samples as KBr
pellets or a liquid film on NaCl plates in a Nippon Denshi JIR-
AQ2OM spectrophotometer. Mass spectra were obtained on a
Nippon Denshi JMS-01SA-2 spectrometer at 75 eV using a
direct-inlet system through GC.
OMe
OMe
i (X+)
(CH2)3
11a
2
X
X
Materials
Preparation of 1,3-bis(5-tert-butyl-2-methoxyphenyl)propane
4 has been previously described.6c
13a X = Br
(62%)
(66%)
(75%)
(77%)
b
c
d
X = CH2Cl
X = CHO
X = COMe
Preparation of 1,3-bis(5-tert-butyl-2-hydroxyphenyl)propane
5. To a solution of 1,3-bis(5-tert-butyl-2-methoxyphenyl)-
propane 4 (10.0 g, 27.1 mmol) in dry CH2Cl2 (180 cm3) at 0 ЊC
was gradually added a solution of BBr3 (4.6 cm3, 48.7 mmol) in
CH2Cl2 (120 cm3) over a period of 30 min. After the reaction
mixture had been stirred at room temp. for 24 h, it was poured
into ice–water (200 cm3) and extracted with CH2Cl2 (100
cm3 × 2). The combined extracts were washed with water (100
cm3 × 2), dried (Na2SO4) and evaporated in vacuo to afford
crude 5 as a colourless solid. Recrystallization of this from hex-
ane gave the title compound 5 (8.3 g, 90%) as prisms; mp 107–
110 ЊC; νmax(KBr)/cmϪ1 3317 (OH); δH (CDCl3) 1.28 (18 H, s),
1.91–2.02 (2 H, m), 2.68 (4 H, t, J 7.6), 4.96 (2 H, s, exchange-
able with D2O), 6.70 (2 H, d, J 8.3), 7.07 (2 H, dd, J 2.4/8.3) and
7.15 (2 H, d, J 2.4); m/z 340 (M
O
O
ii, iii
(CH2)3
7
(75%)
2
14
(80%)
ϩ) (Found: C, 81.20; H, 9.40.
iv
C23H32O2 requires C, 81.13; H, 9.47%).
Base-catalysed condensation: typical procedure
OH
OH
To a vigorously stirred mixture of 5 (5 g, 14.77 mmol) and
paraformaldehyde (895 mg, 29.8 mmol) in p-xylene (150 cm3)
was added under nitrogen 5  aq. NaOH (3 cm3). After
the reaction mixture had been heated at 80 ЊC for 3 h and
refluxed for 16 h, it was cooled to room temp., acidified with 1 
aq. HCl (50 cm3) and extracted with CH2Cl2 (2 × 300 cm3). The
combined extracts were washed with water (100 cm3 × 2), dried
(Na2SO4) and evaporated in vacuo. The residue was washed
with hexane (50 cm3 × 2) to afford crude 6 (4.69 g, 90%) as a
colourless solid. Recrystallization of this from toluene gave
6,13,22,29-tetra-tert-butyl-9,16,25,32-tetrahydroxy[3.1.3.1]-
metacyclophane 6 as prisms; mp 260 ЊC; νmax(KBr)/cmϪ1 3254
(OH); δH (CDCl3) 1.24 (36 H, s), 1.78 (4 H, br s), 2.85 (8 H, br s),
4.01 (4 H, s), 6.94 (4 H, d, J 2.4), 7.15 (4 H, d, J 2.4) and 9.35 (4
H, s, exchangeable with D2O); m/z 704 (Mϩ) (Found: C, 81.70;
H, 9.15. C48H64O4 requires C, 81.77; H, 9.15%).
(CH2)3
2
15
Scheme 6 Reagents and conditions: i, a, Br2, CCl4, room temp. for 1 h;
b, ClCH2OMe, TiCl4, CH2Cl2, room temp. for 24 h; c, Cl2CHOMe,
TiCl4, CH2Cl2, room temp. for 24 h; d, Ac2O, TiCl4, CH2Cl2, room
temp. for 24 h; ii, NaH, DMF, THF, room temp. for 1 h; iii, allyl
bromide, reflux for 3 h; iv, N,N-diethylaniline, reflux (250 ЊC) for 6 h
Conclusions
We have prepared 9,16,25,32-tetrahydroxy[3.1.3.1]MCP 7 in 6
steps from anisole with the tert-butyl group as a positional pro-
tecting group in 27% overall yield using base-catalysed conden-
sation of 1,3-bis(5-tert-butyl-2-hydroxyphenyl)propane 5 with
formaldehyde in xylene. Intramolecular hydrogen bonding has
been observed in the tetraols 6 and 7, although it is slightly
weaker than that in the corresponding calix[4]arenes because of
the flexibility of the propane linkages.
Trans-tert-butylation of 6: typical procedure
To a solution of 6 (2.0 g, 2.84 mmol) in benzene (80 cm3) was
added a solution of AlCl3 (1.44 g, 10.80 mmol) in nitromethane
(3.0 cm3) at 20 ЊC. After being stirred at 20 ЊC for 48 h, the
reaction mixture was poured into ice–water (100 cm3) and
extracted with benzene (100 cm3 × 2). The combined extracts
were washed with water (100 cm3 × 2), dried (Na2SO4) and
evaporated in vacuo to leave a residue. This was chromato-
We have also demonstrated de-tert-butylation of tert-butyl-
[3.1.3.1]MCP 6 and the introduction of sulfonate groups on the
1728
J. Chem. Soc., Perkin Trans. 1, 1997

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graphed on SiO2 with benzene as the eluent to give 9,16,25,32-
tetrahydroxy[3.1.3.1]metacyclophane 7 (1.09 g, 80%) as prisms
(from CHCl3–MeOH, 1:1); mp 170–175 ЊC; νmax(KBr)/cmϪ1
3529 and 3485 (OH); δH (CDCl3) 1.86 (4 H, br s), 2.90 (8 H, br
s), 4.07 (4 H, s), 6.80 (4 H, t, J 7.3), 6.96 (4 H, dd, J 2.4 and 7.3),
7.14 (4 H, dd, J 2.4 and 7.3) and 9.50 (4 H, s, exchangeable with
D2O); m/z 480 (Mϩ) (Found: C, 79.43; H, 6.75. C32H32O4
requires C, 79.97; H, 6.71%).
Similar treatment of 6 with toluene in the presence of AlCl3–
MeNO2 afforded 7. The yields and reaction conditions are
given in Table 2. The formation of tert-butylbenzene 8a and
tert-butyltoluene 8b was confirmed by GLC (conditions: Shi-
madzu gas chromatography, GC-14A, Silicone OV-1, 2 m, pro-
grammed temperature rise 12 ЊC minϪ1; carrier gas nitrogen 25
ml minϪ1).
(12 H, s), 4.20 (4 H, s), 7.07 (4 H, d, J 2.4) and 7.18 (4 H, d,
J 2.4); m/z 848, 850 and 852 (Mϩ) (Found: C, 50.60; H, 4.46.
C36H36O4Br4 requires C, 50.73; H, 4.26%).
Preparation of 6,13,22,29-tetrakis(chloromethyl)-9,16,25,32-
tetramethoxy[3.1.3.1]metacyclophane 13b
To a solution of 11a (100 mg, 0.19 mmol) and ClCH2OMe (0.1
cm3, 1.44 mmol) in CH2Cl2 (10 cm3) was added a solution of
TiCl4 (0.2 cm3, 1.44 mmol) in CH2Cl2 (2 cm3) at room tempera-
ture. After the reaction mixture had been stirred for 24 h, it was
poured into ice–water (10 cm3). The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (10 cm3 × 2).
The combined organic layer and extracts were washed with
water (10 cm3 × 2), dried (Na2SO4) and evaporated in vacuo to
leave a residue which, after column chromatography on silica gel
(Wako, C-300; 50 g) with benzene–CHCl3 (1:1) as eluent,
afforded the title compound 13b (92 mg, 66%) as a colourless
solid. Recrystallization of this from benzene gave 13b as prisms;
mp >300 ЊC; δH (CDCl3) 1.80 (4 H, m), 2.55 (8 H, t, J 7.0), 3.19
(12 H, s), 3.83 (4 H, s), 4.50 (8 H, s), 6.97 (4 H, d, J 2.4) and 7.08
(4 H, d, J 2.4); m/z 728, 730, 732, 734 and 736 (Mϩ) (Found: C,
67.93; H, 6.22. C40H44O4Cl4ؒC6H6 requires C, 68.32; H, 6.23%).
Methylation of 7 with methyl iodide in the presence of NaH
A mixture of 7 (400 mg, 0.832 mmol) and 60% NaH (640.0 mg,
16.0 mmol) in dry tetrahydrofuran (36 cm3) and DMF (9 cm3)
was stirred at room temperature for 1 h under nitrogen. Methyl
iodide (1.29 cm3, 14.18 mmol) was then added to the mixture
after which it was heated under reflux for an additional 3 h.
After cooling to room temperature, the reaction mixture was
acidified with 1  aq. HCl (10 cm3) and extracted with CH2Cl2
(100 cm3 × 2). The combined extracts were washed with water
(50 cm3 × 2), dried (Na2SO4) and evaporated in vacuo to afford
crude 11a as a colourless solid. Recrystallization from hexane–
benzene (1:1) gave 9,16,25,32-tetramethoxy[3.1.3.1]metacyclo-
phane 11a (380 mg, 85%) as prisms; mp 263–266 ЊC; δH (CDCl3)
1.79 (4 H, m), 2.57 (8 H, t, J 7.3), 3.19 (12 H, s), 3.86 (4 H, s),
6.91 (4 H, d, J 7.3), 6.92 (4 H, dd, J 2.0 and 7.3) and 7.03 (4 H,
dd, J 2.0 and 7.3); m/z 536 (Mϩ) (Found: C, 80.60; H, 7.46.
C36H40O4 requires C, 80.56; H, 7.51%).
6,13,22,29-Tetra-tert-butyl-9,16,25,32-tetramethoxy[3.1.3.1]-
metacyclophane 11b was prepared in a similar manner to that
described above in 96% yield as prisms (hexane–benzene, 1:1);
mp >300 ЊC; δH (CDCl3) 1.24 (36 H, s), 1.75–1.81 (4 H, m), 2.53
(8 H, t, J 7.3), 3.14 (12 H, s), 3.83 (4 H, s), 6.97 (4 H, d, J 2.4)
and 7.01 (4 H, d, J 2.4); m/z 760 (Mϩ) (Found: C, 81.86; H, 9.44.
C52H72O4 requires C, 82.06; H, 9.53%).
Preparation of 6,13,22,29-tetraformyl-9,16,25,32-tetra-
methoxy[3.1.3.1]metacyclophane 13c
To a solution of 11a (100 mg, 0.19 mmol) and Cl2CHOMe (0.3
cm3, 2.53 mmol) in CH2Cl2 (10 cm3) was added a solution of
TiCl4 (0.2 cm3, 1.44 mmol) in CH2Cl2 (2 cm3) at room tempera-
ture. After the reaction mixture had been stirred for 24 h, it was
poured into ice–water (10 cm3). The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (10 cm3 × 2).
The combined organic layer and extracts were washed with
water (10 cm3 × 2), dried (Na2SO4) and evaporated in vacuo to
leave a residue which, after column chromatography on silica
gel (Wako, C-300; 50 g) with benzene–CHCl3 (1:1) as eluent,
afforded the title compound 13c (92 mg, 75%) as a colourless
solid. Recrystallization of this from CHCl3–MeOH (1:1) gave
13c as prisms; mp >300 ЊC; νmax(KBr)/cmϪ1 1690 (C᎐O);
᎐
δH (CDCl3) 1.83 (4 H, m), 2.57 (8 H, t, J 7.0), 3.23 (12 H, s), 3.93
(4 H, s), 7.47 (4 H, d, J 2.4), 7.57 (4 H, d, J 2.4) and 9.81 (4 H,
s); m/z 648 (Mϩ) (Found: C, 72.03; H, 6.30. C40H40O8ؒMeOH
requires C, 72.33; H, 6.51%).
Preparation of tetrasodium 9,16,25,32-tetrahydroxy[3.1.3.1]-
metacyclophane-6,13,22,29-tetrasulfonate 12
Compound 7 (1.0 g, 2.08 mmol) was mixed with concentrated
H2SO4 (10 cm3) and the mixture was heated at 60 ЊC for 6 h,
after which it was cooled and filtered. The precipitate recovered
was dissolved in water (50 cm3), and the solution was neutral-
ized by BaCO3. Precipitated BaSO4 was filtered off and Na2CO3
was added to the filtrate to bring it to pH 8–9; the reaction
mixture was then left overnight at room temperature. The pre-
cipitate was filtered to afford the title compound 12 (1.0 g, 54%)
as a colourless powder; mp >300 ЊC; νmax(KBr)/cmϪ1 3425,
1601, 1592, 1486, 1297, 1163, 1119, 1049, 675, 667, 657, 639 and
620; δH (D2O) 1.55 (4 H, m), 2.63 (8 H, t, J 8.4), 3.90 (4 H, s),
7.37 (4 H, d, J 2.4) and 7.38 (4 H, d, J 2.4).
Preparation of 6,13,22,29-tetraacetyl-9,16,25,32-tetramethoxy-
[3.1.3.1]metacyclophane 13d
To a solution of 11a (200 mg, 0.37 mmol) and acetic anhydride
(0.4 cm3, 2.16 mmol) in CH2Cl2 (20 cm3) was added a solution
of TiCl4 (1.0 cm3, 8.64 mmol) in CH2Cl2 (3 cm3) at room tem-
perature. After the reaction mixture had been stirred for 24 h, it
was poured into ice–water (10 cm3) and the layers separated.
The aqueous layer was extracted with CH2Cl2 (10 cm3 × 2) and
the combined organic layer and extracts were washed with
water (10 cm3 × 2), dried (Na2SO4) and evaporated in vacuo to
leave a residue. This, when column chromatographed on silica
gel (Wako, C-300; 50 g) with benzene–CHCl3 (1:1) as eluent,
afforded the title compound 13d (200 mg, 77%) as a colourless
solid. Recrystallization of this from CHCl3–MeOH (1:1) gave
Preparation of 6,13,22,29-tetrabromo-9,16,25,32-tetramethoxy-
[3.1.3.1]metacyclophane 13a
13d as prisms; mp >300 ЊC; νmax(KBr)/cmϪ1 1690 (C᎐O);
᎐
To a solution of 11a (100 mg, 0.19 mmol) in CCl4 (10 cm3) was
added a small amount of iron powder and a solution of Br2 (0.2
cm3, 3.6 mmol) in CCl4 (2 cm3) at room temperature. After the
reaction mixture had been stirred for 1 h, it was poured into
water (10 cm3). The organic layer was separated and the aque-
ous layer was extracted with CH2Cl2 (10 cm3 × 2). The com-
bined organic layer and extracts were washed with water (10
cm3 × 2), dried (Na2SO4) and evaporated in vacuo to leave a
residue, which was washed with hexane (5 cm3) to afford the
title compound 13a (100 mg, 62%) as a colourless solid.
Recrystallization of this from benzene gave 13a as prisms; mp
130–135 ЊC; δH (CDCl3) 1.79 (4 H, m), 2.50 (8 H, t, J 7.3), 3.22
δH (CDCl3) 1.88 (4 H, m), 2.53 (12 H, s), 2.63 (8 H, t, J 7.0), 3.27
(12 H, s), 3.95 (4 H, s), 7.62 (4 H, d, J 2.4) and 7.69 (4 H, d, J
2.4); m/z 704 (Mϩ) (Found: C, 75.03; H, 6.70. C44H48O8 requires
C, 74.98; H, 6.86%).
Preparation of 9,16,25,32-tetraallyloxy[3.1.3.1]metacyclophane
14
A mixture of 7 (400 mg, 0.567 mmol) and 60% NaH (640.0 mg,
16.0 mmol) in dry tetrahydrofuran (36 cm3) and DMF (9 cm3)
was stirred at room temperature for 1 h under nitrogen. Allyl
bromide (1.20 cm3, 14.18 mmol) was then added to the mixture
after which it was heated under reflux for an additional 3 h.
J. Chem. Soc., Perkin Trans. 1, 1997
1729

View Article Online
2404; (b) T. Yamato, Y. Saruwatari, S. Nagayama, K. Maeda and
After cooling to room temperature, the mixture was acidified
with 1  aq. HCl (10 cm3) and extracted with CH2Cl2 (100
cm3 × 2). The combined extracts were washed with water (50
cm3 × 2), dried (Na2SO4) and evaporated in vacuo to afford a
yellow oil. The excess of unchanged allyl bromide was removed
from this by distillation under reduced pressure using a Kugel-
rohr apparatus and the residue was washed with hexane to
afford the title compound 14 (400 mg, 75%) as a colourless solid.
Recrystallization of this from CHCl3–MeOH (1:1) gave 14 as
prisms; mp 185–190 ЊC; δH (CDCl3) 1.82 (4 H, br s), 2.51 (8 H, br
s), 3.85 (8 H, d, J 5.5), 3.86 (4 H, br s), 4.78 (4 H, dd, J 1.8 and
10.4), 5.04 (4 H, dd, J 1.83 and 17.7), 5.46–5.62 (4 H, m), 6.89 (4
H, t, J 7.3), 6.92 (4 H, dd, J 1.2 and 7.3) and 7.02 (4 H, dd, J 1.2
and 7.3); m/z 640 (Mϩ) (Found: C, 82.63; H, 7.55. C44H48O4
requires C, 82.46; H, 7.55%).
M. Tashiro, J. Chem. Soc., Chem. Commun., 1992, 861; (c)
F. Vögtle, J. Schmitz and M. Nieger, Chem. Ber., 1992, 125, 2523; (d)
T. Yamato, K. Hasegawa, Y. Saruwatari and L. K. Doamekpor,
Chem. Ber., 1993, 126, 1435; (e) T. Yamato, Y. Saruwatari, L. K.
Doamekpor, K. Hasegawa and M. Koike, Chem. Ber., 1993, 126,
2501.
6 (a) T. Yamato, J. Matsumoto, M. Kajihara and M. Tashiro, Chem.
Express, 1990, 5, 769; (b) T. Yamato, J. Matsumoto, S. Ide,
K. Tokuhisa, K. Suehiro and M. Tashiro, J. Org. Chem., 1992, 57,
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8 (a) C. D. Gutsche, Acc. Chem. Res., 1983, 16, 161; (b) C. D. Gutsche
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Preparation of 6,13,22,29-tetraallyl-9,16,25,32-tetrahydroxy-
[3.1.3.1]metacyclophane 15
9 M. F. Semmelhack, J. J. Harrison, D. C. Young, A. Gutiérrez,
S. Rafii and J. Clardy, J. Am. Chem. Soc., 1985, 107, 7508.
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11 C. D. Gutsche and J. A. Levine, J. Am. Chem. Soc., 1982, 104, 2652.
12 (a) S. Shinkai, S. Mori, T. Tsubaki, T. Sone and O. Manabe,
Tetrahedron Lett., 1984, 25, 5315; (b) S. Shinkai, H. Koreishi,
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A solution of 14 (500 mg, 0.780 mmol) in N,N-diethylaniline
(50 cm3) was heated under reflux (250 ЊC) for 6 h in a flow of
nitrogen after which it was cooled. Excess of N,N-diethylaniline
was removed by distillation under reduced pressure (1 mmHg)
to leave a residue which was washed with hexane (10 cm3) to
afford the title compound 15 (400 mg, 80%) as a colourless solid.
Recrystallization of this from CHCl3–MeOH (1:1) gave 15 as
prisms; mp 95–100 ЊC; δH (CDCl3) 1.80 (4 H, br s), 2.80 (8 H, br
s), 3.23 (8 H, d, J 6.4), 3.96 (4 H, br s), 5.02 (4 H, dd, J 1.8 and
10.4), 5.06 (4 H, dd, J 1.8 and 17.7), 5.8–6.0 (4 H, m), 6.76 (4 H,
d, J 2.0), 6.95 (4 H, d, J 2.0) and 9.31 (4 H, s); m/z 640 (Mϩ)
(Found: C, 82.50; H, 7.39. C44H48O4 requires C, 82.46; H,
7.55%).
14 (a) J.-D. van Loon, R. G. Janssen, W. Verboom, and D. N.
Reinhoudt, Tetrahedron Lett., 1992, 33, 5125; (b) P. D. Beer,
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References
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Paper 6/06358F
Received 16th September 1996
Accepted 5th February 1997
5 (a) M. Tashiro, A. Tsuge, T. Sawada, T. Makishima, S. Horie,
T. Arimura, S. Mataka and T. Yamato, J. Org. Chem., 1990, 55,
1730
J. Chem. Soc., Perkin Trans. 1, 1997