Facile preparation and molecular structure of a novel metacyclophane

Article abstract of DOI:10.1080/00397910802138645

A novel 1,1,10,10,19,19-hexamethyl-5,14,23-trimethoxy[3.3.3]metacyclophane (2) was prepared in 25% yield by Friedel-Crafts cyclization of 4-(2-methoxyphenyl)-2-methylbutan-2-ol (1) at - 78°C using TiCl4 as Lewis acid catalyst in anhydrous dichloromethane. The structure of cyclophane 2 was determined by single-crystal X-ray diffraction, and the impact of substrate concentration on the yield of macrocycle 2 was also examined. The study on the effect of substituents at the phenyl ring showed that the methoxy group in 1 is crucial for its trimerization to give the hexamethyl[3.3.3]metacyclophane derivative. Demethylation of 2 with BBr3 gave 1,1,10,10,19,19-hexamethyl-5,14, 23-trihydroxy[3.3.3]metacyclophane (4) in 96% yield, and its three hydroxyl groups provide the possible modification sites for further construction of supramolecular assemblies. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802138645

Synthetic Communications1, 38: 2341–2348, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802138645
Facile Preparation and Molecular Structure
of a Novel Metacyclophane
Jing-Lei Zhang, Qi Shi, Jiang Wu, and Yang Wang
Department of Medicinal Chemistry, School of Pharmacy,
Fudan University, Shanghai, China
Abstract: A novel 1,1,10,10,19,19-hexamethyl-5,14,23-trimethoxy[3.3.3]metacy-
clophane (2) was prepared in 25% yield by Friedel–Crafts cyclization of 4-
(2-methoxyphenyl)-2-methylbutan-2-ol (1) at ꢀ78 ꢁC using TiCl4 as Lewis acid
catalyst in anhydrous dichloromethane. The structure of cyclophane 2 was
determined by single-crystal X-ray diffraction, and the impact of substrate
concentration on the yield of macrocycle 2 was also examined. The study on
the effect of substituents at the phenyl ring showed that the methoxy group in
1 is crucial for its trimerization to give the hexamethyl[3.3.3]metacyclophane
derivative. Demethylation of 2 with BBr3 gave 1,1,10,10,19,19-hexamethyl-
5,14,23-trihydroxy[3.3.3]metacyclophane (4) in 96% yield, and its three hydroxyl
groups provide the possible modification sites for further construction of supra-
molecular assemblies.
Keywords: 1-(3-Chloro-3-methylbutyl)-2-methoxybenzene; Friedel-Crafts
cyclization; 1,1,10,10,19,19-hexamethyl-5,14,23-trimethoxy[3.3.3]metacyclophane;
4-(2-methoxyphenyl)-2-methylbutan-2-ol
INTRODUCTION
Host–guest chemistry has been developing rapidly in the past several dec-
ades.[1] Many macrocyclic compounds were employed as host molecules.
Particularly, cyclodextrins and calixarenes have attracted major interest,
because they can form inclusion complexes with various hydrophobic
guests in aqueous solution. Calixarenes fundamentally consist of phenol
Received August 16, 2007
Address correspondence to Yang Wang, Department of Medicinal Chemistry,
School of Pharmacy, Fudan University, Shanghai 200032, China. E-mail:
wangyang@shmu.edu.cn
2341

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J.-L. Zhang et al.
rings that are connected to each other by methylene bridges at meta posi-
tions of the ring, and thus, are considered as members of the metacyc-
lophane (MCP) family. So far, there has been a lot of work on the
syntheses, conformation and inclusion properties of macrocyclic cyclo-
phanes[2] in which, the designing of artificial cavities of various sizes is
possible. However, the preparations of macrocyclophanes are not easy,
which usually contain several steps including oligomerization with low
yields of 20% or less due to poor regiochemical control.[3,4] In this work,
We report a one-step preparation of 1,1,10,10,19,19-hexamethyl-5,14,23-
trimethoxy[3.3.3]metacyclophane (2), its crystal structure and its
demethylated derivative (4).
RESULTS AND DISCUSSION
1,1,10,10,19,19-hexamethyl-5,14,23-trimethoxy[3.3.3]metacyclophane (2)
was prepared in 25% yield from 4-(2-methoxyphenyl)-2-methylbutan-2-
ol (1) by Friedel-Crafts cyclization using TiCl4 as the catalyst[5] under
ꢀ78 ꢁC in anhydrous dichloromethane. 1-(3-chloro-3-methylbutyl)-2-
methoxybenzene (3) was also obtained in 14% yield due to nucleophilic
substitution of hydroxyl group in 1 by chloridion. Demethylation of 2
was carried out by reaction with BBr3 leading to 1,1,10,10,19,19-hexa-
methyl-5,14,23-trihydroxy[3.3.3]metacyclophane (4) in 96% yield. The
three hydroxyl groups in 4 provide the possible modification sites for
further construction of supramolecular assemblies.
The molecular structure of 2 was determined by single crystal X-ray
crystallographic analysis (Fig. 1). Three phenyl rings incline into the
cavity with different dihedral angles with the mean plane of the molecule
and three methoxy groups pointing outward. Both molecules’ bond
angles and bond lengths are unexceptional.
The impact of substrate concentration on the yield of macrocycle 2
was also examined. As shown in Table 1, the yields of product 2 did

Facile Preparation and Molecular Structure of a Novel Metacyclophane
2343
˚
Figure 1. Molecular structure of compound 2. Selected atom distances in A:
C(5)–C(17), 5.206; C(17)–C(29), 5.443; C(29)–C(5), 4.895; C(5)–C(20), 5.737;
C(17)–C(32), 6.380; C(29)–C(8), 6.351; C(2)–C(14), 8.863; C(14)–C(26), 8.899;
C(26)–C(2), 9.257; O(1)–O(2), 9.387; O(2)–O(3), 9.395; O(3)–O(1), 10.123;
C(12)–C(24), 11.564; C(24)–C(36), 11.057; C(36)–C(12), 12.475.
not change very much with the concentration range of 1 from 1.1 to
2.7 mg=mL. However, further increasing of the substrate concentration
to 3.6 mg=mL was obviously unfavorable to the formation of 2, probably
because of the easy formation of oligomers or polymers. A big spot with
Rf ¼ 0 (Eluent: petroleum ether-EtOAc (20:1 v=v)) was observed by TLC
monitor in every case.
Table 1. Distributions of products 2 and 3 under different substrate concen-
tration (HPLC yield%)
Substrate 1 = CH2Cl2 (mg = mL)
Product 2
Product 3
111=100 ¼ 1.1
105=50 ¼ 2.1
400=150 ¼ 2.7
108=30 ¼ 3.6
25%
26%
27%
14%
16%
13%
15%
16%

2344
J.-L. Zhang et al.
The scope of the present synthetic method was further investigated
by taking 4-(2-substituted phenyl)-2-methylbutan-2-ol (5a,b) having a
weak electron-donating (methyl) or electron withdrawing (bromo) group,
as the reactants under the same conditions. The cyclization of 5a gave the
chlorinated product, 1-(3-chloro-3-methylbutyl)-2-methylbenzene (6a),
and an intramolecular cyclization product, 1,1,4-trimethyl-2,3-dihydro-
1H-indene (7), in 40% and 51% yields, respectively. In the reaction of
5b, only a chlorinated product, 1-(3-chloro-3-methylbutyl)-2-bromoben-
zene (6b), was obtained in 43% yield, while some very polar unidentified
matters were also observed on silica gel TLC plate (Rf value ¼ 0 with
ethyl acetate as eluent). No hexamethyl[3.3.3]metacyclophane derivatives
were observed in the reactions of these two substrates with either methyl
or bromo substituent at the benzene ring, which clearly showed that the
methoxy group of 1 plays an important role in its trimerization to give
the hexamethyl[3.3.3]metacyclophane derivative.
In summary, a facile synthesis of 1,1,10,10,19,19-hexamethyl-
5,14,23-trimethoxy[3.3.3]metacyclophane (2) and 1,1,10,10,19,19-
hexamethyl-5,14,23-trihydroxy[3.3.3]metacyclophane (4) was realized
from 4-(2-methoxyphenyl)-2-methylbutan-2-ol (1) by Friedel–Crafts
cyclization and demethylation. The comparison of the substituent effect
in the reactions of substrate 1 and 5a,b clearly demonstrated that the
methoxy group of 1 is crucial for its trimerization to give the correspond-
ing hexamethyl[3.3.3]metacyclophane derivative. Further work will
focus on the structural properties of these new macrocycles and utilizing
them for the construction of supramolecular assemblies.
EXPERIMENTAL
Melting points were uncorrected. Reactions were monitored by TLC on
0.2 -mm silica-gel plates, and the spots were visualized by ultraviolet light.
Flash-column chromatography was performed on silica gel (300–400
mesh). 1H NMR and 13C NMR spectra were recorded on a Varian Mer-
cury 300 spectrometer at 300.13 and 75.47 MHz, respectively, and the sol-
vent used was CDCl3 unless indicated. All chemical shifts were reported
in d units with reference to TMS (1H) or the signals of the solvent (13C).

Facile Preparation and Molecular Structure of a Novel Metacyclophane
2345
Mass spectra were taken on an HP5989A, Agilent 5973N MSD (EI), or
Agilent LC=MSD spectrometer (ESI). High resoultion mass spectra
(HRMS) data were determined on a Waters Micromass GCT spectrometer.
Cyclization of Compound 1 with TiCl4
A solution of 1 (400 mg, 2.06 mmol) in 150 mL of anhydrous CH2Cl2 was
added dropwise over a period 1.5 h to a solution of TiCl4 (0.8 mL, 1.376 g,
7.25 mmol) in 8 mL of anhydrous CH2Cl2 with stirring at ꢀ78 ꢁC under
an argon atmosphere. The reaction mixture changed into red gradually
and was stirred at room temperature overnight after addition was com-
plete. Then it was poured into saturated aqueous NaHCO3, and the
layers were separated. The aqueous layer was extracted with EtOAc
(3 ꢂ 30 mL), and the combined organic phase was washed with H2O
(3 ꢂ 20 mL) and brine (20 mL) and dried over Na2SO4. After removal
of the volatiles in vacuo, the residue was purified by flash column chro-
matography on silica gel (petroleum ether, petroleum ether-AcOEt
1
(20:1 v=v)) to give compound 3 as a clear oil (60 mg, 14%): H NMR
(300 MHz, CDCl3) d: 1.65 (s, 6H, CH3), 2.01 (t, J ¼ 7.8 Hz, 2H, 3-H),
2.80 (t, J ¼ 8.4 Hz, 2H, 4-H), 3.82 (s, 3H, OCH3), 6.83–6.89 (m, 2H, 30-
H, 50-H), 7.14–7.20 (m, 2H, 40-H, 60-H).13C NMR (75 MHz, CDCl3) d:
157.39, 130.12, 129.73, 127.18, 120.45, 110.20, 71.047, 55.22, 45.98,
32.34, 29.69, 26.24. MS (EI) m=z (%): 212 (Mþ , 9.44), 176 (9.84), 161
(16.31), 121 (68.89), 91 (100.00). HRMS: Calcd for C12H17OCl:
212.0968; Found: 212.0974. Compound 2 as white prisms (90 mg,
ꢁ
1
25%): mp: 144–146 C. H NMR (300 MHz, CDCl3) d: 1.30 (s, 18H),
1.92–1.98 (m, 6H), 2.42–2.48 (m, 6H), 3.82 (s, 9H), 6.77 (d, J ¼ 8.1 Hz,
3H), 7.13–7.16 (m, 6H).13C NMR (75 MHz, CDCl3) d: 155.15, 141.41,
131.12, 126.62, 123.57, 108.39, 60.40, 55.28, 43.65, 37.21, 29.47, 25.43,
21.07, 14.19. ESI-MS m=z (%): 546.40 (M þ NH4 þ , 100).
X-ray Crystal Structure Determination of 1,1,10,10,19,19-hexamethyl-
5,14,23-trimethoxy[3.3.3]metacyclophane (2)
Crystals of compound 2 suitable for single-crystal X-ray diffraction were
grown by slow evaporation of an ethyl acetate solution of 2. Crystal with
dimensions of 0.497 mm ꢂ 0.236 mm ꢂ 0.135 mm was selected and
mounted on a Bruker Smart CCD diffractometer with graphite mono-
chromatized Mo Ka radiation (k ¼ 0.071073 nm). Diffraction data were
collected using x-2h scans at room temperature (293 K). A perspective
view of the structure is depicted in Figure 1. Empirical formula:
C36H48O3. Formula weight: 528.74. Crystal system: orthorhombic. Space

2346
J.-L. Zhang et al.
´
´
˚
˚
group: Pca2(1). Unit cell dimensions: a ¼ 24.763 (4) A, b ¼ 11.0549 (17) A,
´
´
3
˚
˚
c ¼ 11.5301 (18) A, V ¼ 3156.4 (8) A . Theta range for data collection
is from 1.64 to 25.49ꢁ. Z ¼ 4. Dc ¼ 1.113 g=cm3. F(000) ¼ 1152.
Refinement method: full-matrix least-squares on F2. Goodness-of-fit
on F2: 0.851. Final R indices [I > 2r (I)]: 0.0786, 0.2028. R indices (all
data): 0.1425, 0.2301. Largest diff. peak and hole: 0.667 and
ꢀ0.294 e=nm3.
Full crystallographic details have been deposited at Cambridge Crys-
tallographic Data Centre (CCDC). Any request to the CCDC for this
material should quote the full literature citation and the reference number
CCDC 653771.
1,1,10,10,19,19-hexamethyl-5,14,23-trihydroxy[3.3.3]metacyclophane (4)
To a solution of 2 (80 mg, 0.15 mmol) in 2 mL of dry CH2Cl2, BBr3
(0.3 mL, 3 M in CH2Cl2) was added dropwise with stirring at
ꢀ 78 ꢁC under an argon atmosphere. After addition was complete,
the reaction mixture was warmed to room temperature and stirred
for another 2.5 h. The mixture was then added to ice water, and the
precipitate was filtered. The aqueous mixture was extracted with
CH2Cl2 (3 ꢂ 20 mL). The organic layer was washed with water and
brine, dried over Na2SO4, and evaporated toꢁ leave compound 4 as a
1
pale yellow solid (70 mg, 96%): mp 118–120 C. H NMR (300 MHz,
CDCl3) d: 1.31 (s, 6H, CH3), 1.98 (t, J ¼ 8.2 Hz, 6H), 2.44 (t,
J ¼ 8.2 Hz, 6H), 4.57 (br, 3H), 6.70 (d, J ¼ 8.2 Hz, 3H), 7.07 (d,
J ¼ 13.3 Hz, 6H). MS (EI) m=z (%): 486 (Mþ , 18.46), 323 (44.04),
203 (30.95), 163 (100.00), 155 (24.70), 147 (62.56). HRMS: calcd. for
C33H42O3: 486.3134; found: 486.3114.
Reaction of Compound 5a with TiCl4
Following a similar procedure for the cyclization of compound 1 with
TiCl4, 6a and 7 (Rf ¼ 0.6 and 0.8, on silica-gel plate with petroleum ether
as the eluent) were afforded from 5a as colorless liquids in 40% and 51%
yields respectively. 6a: 1H NMR (400 MHz, CDCl3) d: 1.27 (s, 6H, CH3),
1.94 (t, J ¼ 7.1 Hz, 2H, 20-H), 2.31 (s, 3H, CH3), 2.83 (t, J ¼ 7.3 Hz, 2H,
10-H), 6.98–7.01 (m, 2H, 3-H, 5-H), 7.11–7.16 (m, 2H, 4-H, 6-H). MS (EI)
m=z (%): 196 (Mþ , 5.61), 145 (39.28), 85 (45.36), 71 (70.03), 69 (43.33),
1
57 (100.00), 55 (49.78), 43 (75.40), 41 (59.99). 7: H NMR (400 MHz,
CDCl3) d: 1.26 (s, 6H, 1-CH3), 1.93 (t, J ¼ 7.5 Hz, 2H, 2-H), 2.27 (s, 3H,
4-CH3), 2.82 (t, J ¼ 7.4 Hz, 2H, 3-H), 6.98–7.00 (m, 2H, 7-H, 5-H),
7.10–7.14 (m, 1H, 6-H).[6]

Facile Preparation and Molecular Structure of a Novel Metacyclophane
Reaction of Compound 5b with TiCl4
2347
Following a similar procedure for the cyclization of compound 1 with
1
TiCl4, 6b was obtained from 5b as a colorless liquid in 43% yield: H
NMR (400MHz, CDCl3) d: 1.70 (s, 6H, CH3), 2.09–2.13 (m, 2H, 20-H),
2.87–2.91 (m, 2H, 10-H), 7.24–7.28 (m, 2H, 3-H, 5-H), 7.34–7.37 (m,
2H, 4-H, 6-H). MS (EI) m=z (%): 260 (Mþ , 1.00), 91 (30.98), 85
(44.95), 83 (25.76), 71 (78.93), 69 (26.35), 57 (100.00), 55 (35.69), 43
(54.23).
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (No.
20672022) for financial support.
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