Synthesis, modification, and characterization of a family of homologues of exo-calix[4]arene: exo-[n.m.n.m]Metacyclophanes, n,m ≥ 3

Article abstract of DOI:10.1021/jo0003044

A general strategy for the preparation of the family of exo-[n.m.n.m]metacyclophanes (n,m ≥ 3) in 6-steps (starting from 2-bromoanisole)that utilizes a [2 + 2] approach to furnish the exometacyclophane ring in good to moderate yield is described. The soluble copper catalyst [CuBr- LiSPh-LiBr-THF] is used to efficiently couple Grignard and alkyl or ether tosylate reagents in several of the synthetic steps, including the ring construction in the final step. The exo-[n.m.n.m]- metacyclophane ring is conformationally mobile on the NMR time scale, and X-ray crystallography reveals that exo-[3.3.3.3]metacyclophane 2a assumes a cone conformation, and that exo-[6.6.6.6]- metacyclophane 6a assumes a chair conformation. Molecular mechanics calculations show that both conformations for each exo-metacyclophane are very similar in energy. Regiocontrol over the alkylation and acylation of the phenolic oxygens of 2b is problematic, although the preparation of the tetraacetylated 18 and alkylation of 2b with CH₂BrCl to furnish the methylene-linked mono- and bis-adducts 19 and 20 are straightforward.

Full text of DOI:10.1021/jo0003044

J . Org. Chem. 2000, 65, 5185-5196
5185
Syn th esis, Mod ifica tion , a n d Ch a r a cter iza tion of a F a m ily of
Hom ologu es of exo-Ca lix[4]a r en e: exo-[n .m .n .m ]Meta cyclop h a n es,
n ,m g 3
Dennis H. Burns,* Ho-Kit Chan,† J effrey D. Miller,‡ Charles L. J ayne, and
David M. Eichhorn§
Department of Chemistry, Wichita State University, Wichita, Kansas 67260
burns@wsuhub.uc.twsu.edu
Received March 6, 2000
A general strategy for the preparation of the family of exo-[n.m.n.m]metacyclophanes (n,m g 3) in
6-steps (starting from 2-bromoanisole) that utilizes a [2 + 2] approach to furnish the exo-
metacyclophane ring in good to moderate yield is described. The soluble copper catalyst [CuBr-
LiSPh-LiBr-THF] is used to efficiently couple Grignard and alkyl or ether tosylate reagents in
several of the synthetic steps, including the ring construction in the final step. The exo-[n.m.n.m]-
metacyclophane ring is conformationally mobile on the NMR time scale, and X-ray crystallography
reveals that exo-[3.3.3.3]metacyclophane 2a assumes a cone conformation, and that exo-[6.6.6.6]-
metacyclophane 6a assumes a chair conformation. Molecular mechanics calculations show that
both conformations for each exo-metacyclophane are very similar in energy. Regiocontrol over the
alkylation and acylation of the phenolic oxygens of 2b is problematic, although the preparation of
the tetraacetylated 18 and alkylation of 2b with CH2BrCl to furnish the methylene-linked mono-
and bis-adducts 19 and 20 are straightforward.
In tr od u ction
tions.11 Due to the greater number of phenolic rings in
the larger calixarenes, there has been an associated
difficulty with regiochemical control in the chemical
modification of the macrocycle’s upper and lower rims.
The larger calix[n]arenes (n > 4) possess a larger number
of possible ring conformations,12 (calix[6]arene has eight
The development of molecular devices prepared from
calix[4]arenes (tetrahydroxy[1.1.1.1]metacyclophane) is
of current interest.1 Applications of modified calix[4]-
arenes as enzyme and antibody mimics,2 metal-oxo
surface mimics,3 extractants for decontamination,4 sen-
sors and diagnostics,5 molecular magnets,6 photochemical
and electron-transfer devicies,7 porous surfactants,8 and
their use in ISEs9 and nonlinear optical and liquid
crystalline systems10 have all been recently reported.
Only a few examples of calix[n]arenes (n > 4) with a
larger annulus have been utilized as building blocks for
the fabrication of molecular systems with defined func-
(5) For a review, see: (a) Diamond, D.; McKervey, M. A. Calixarene-
based Sensing Agents. Chem. Soc. Rev. 1996, 25, 15-24. For a small
selection of recent examples, see: (b) Bu¨gler, J .; Sommerdijk, N.;
Visser, J .; van Hoek, A.; Nolte, R.; Engbersen, J .; Reinhoudt, D. N. J .
Am. Chem. Soc. 1999, 121, 28-33. (c) Bu¨gler, J .; Engbersen, J .;
Reinhoudt, D. N. J . Org. Chem. 1998, 63, 5339-5344. (d) Matsumoto,
H.; Shinkai, S. Tetrahedron Lett. 1996, 37, 77-80. (e) Zhang, L.; Coffer,
J . L.; Wang, J .; Gutsche, C. D. J . Am. Chem. Soc. 1996, 118, 12840-
12841. (f) Koh, K. N.; Araki, K.; Ikeda, A.; Otsuka, H.; Shinkai, S. J .
Am. Chem. Soc. 1996, 118, 755-758. (g) Steemers, F. J .; Verboom,
W.; Reinhoudt, D. N.; van der Tol, E. B.; Verhoeven, J . W. J . Am. Chem.
Soc. 1995, 117, 9408-9414.
(6) (a) Rajca, A.; Rajca, S.; Desai, S. R. J . Am. Chem. Soc. 1995,
117, 806-816. (b) Rajca, A.; Rajca, S.; Padmakumar, R. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2091-2093.
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Am. Chem. Soc. 1999, 121, 14-27. (b) Ferguson, G.; Gallagher, J . F.;
Lough, A. J .; Notti, A.; Pappalardo, S.; Parisi, M. F. J . Org. Chem.
1999, 64, 5876-5885.
† Present Address: Discovery Chemistry Research, Lilly Research
Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
‡ Present Address: PE Biosystems-LCMS, 500 Old Connecticut
Path, Framingham, MS 01707.
§ Responsible for X-ray crystal analysis.
(1) For general reviews, see: (a) Gutsche, C. D. Calixarenes
Revisited. In Monographs in Supramolecular Chemistry; Stoddart, J .
F., Ed.; Royal Society of Chemistry: London, 1998. (b) Bo¨hmer, V.
Angew. Chem., Int. Ed. Engl. 1995, 34, 713-745. (c) Calixarenes, A
Versatile Class of Macrocyclic Compounds; Vicens, J ., Bo¨hmer, V., Eds;
Kluwer: Dordrecht, The Netherlands, 1991.
(8) Markowitz, A.-F.; J anout, V.; Castner, D. G.; Regen, S. L. J . Am.
Chem. Soc. 1989, 111, 8192-8200.
(9) Brzo´zka, Z. Potentiometric Sensors. In Comprehensive Supra-
molecular Chemistry, Vol. 10; Reinhoudt, D. N., Ed.; Pergamon:
Oxford, 1996.
(2) (a) Molenveld, P.; Engbersen, J .; Reinhoudt, D. N. J . Org. Chem.
1999, 64, 6337-6341. (b) Molenveld, P.; Stikvoort, W.; Kooijman, H.;
Spek, A.; Engbersen, J .; Reinhoudt, D. N. J . Org. Chem. 1999, 64,
3896-3906. (c) Park, H.; Lin, Q.; Hamilton, A. D. J . Am. Chem. Soc.
1999, 121, 8-13. (d) Xie, D.; Gutsche, C. D. J . Org. Chem. 1998, 63,
9270-9278. (e) Molenveld, P.; Engbersen, J .; Kooijman, H.; Spek, A.;
Reinhoudt, D. N. J . Am. Chem. Soc. 1998, 120, 6726-6737.
(3) (a) Giannini, L.; Guillemot, G.; Solari, E.; Floriani, C.; Re, N.;
Chiesi-Villa, A.; Rizzoli, C. J . Am. Chem. Soc. 1999, 121, 2797-2807.
(b) Giannini, L.; Solari, E.; Dovesi, S.; Floriani, C.; Re, N.; Chiesi-Villa,
A.; Rizzoli, C. J . Am. Chem. Soc. 1999, 121, 2784-2796. (c) Giannini,
L.; Caselli, A.; Solari, E.; Floriani, C.; Chiesi-Villa, A.; Rizzoli, C.; Re,
N.; Sgamellotti, A. J . Am. Chem. Soc. 1997, 119, 9709-9719.
(4) (a) Lambert, T. N.; Dasaradhi, L.; Huber, V. J .; Gopalan, A. S.
J . Org. Chem. 1999, 64, 6097-6101. (b) Davis, J . T.; Tirumala, S. K.;
Marlow, A. L. J . Am. Chem. Soc. 1997, 119, 5271-5272, and references
therein.
(10) (a) Kenis, P.; Noordman, O.; Uoubrechts, S.; van Hummel, G.;
Harkema, S.; van Veggel, F.; Clays, K.; Engbersen, J .; Persoons, A.;
van Hulst, N.; Reinhoudt, D. N. J . Am. Chem. Soc. 1998, 120, 7875-
7883. (b) Xu, B.; Swager, T. M. J . Am. Chem. Soc. 1995, 117, 5011-
5012. (c) Xu, B.; Swager, T. M. J . Am. Chem. Soc. 1993, 115, 1159-
1160.
(11) (a) Zhang, L.; Hendel, R. A.; Cozzi, P. G.; Regen, S. L. J . Am.
Chem. Soc. 1999, 121, 1621-1622. (b) Hendel, R. A.; Nomura, E.;
J anout, V.; Regen, S. L. J . Am. Chem. Soc. 1997, 119, 6909-6918. (c)
Lee, W.; Hendel, R. A.; Dedek, P.; J anout, V.; Regen, S. L. J . Am. Chem.
Soc. 1995, 117, 10599-10600. (d) Lee, W.; Hendel, R. A.; Dedek, P.;
J anout, V.; Regen, S. L. J . Am. Chem. Soc. 1995, 117, 6793-6794. (e)
Dedek, P.; J anout, V.; Regen, S. L. J . Org. Chem. 1993, 58, 6553-
6555.
(12) Ikeda, A.; Shinkai, S. Chem. Rev. 1997, 97, 1713-1734.
10.1021/jo0003044 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/03/2000

5186 J . Org. Chem., Vol. 65, No. 17, 2000
Burns et al.
Sch em e 1
possible conformations, for example), and when chemi-
cally modified the number of possible structures only
increases. Both of these complications have limited their
use in molecular devices. A way to increase the size of
the annulus of a calixarene, and yet avoid the difficulties
associated with an increase in the number of phenolic
rings, is to prepare tetrahydroxy[n.n.n.n]metacyclo-
phanes, n > 1. Little attention has been paid to these
higher methylene homologues of calix[4]arenes, even
though their larger cavity size and different shape makes
their supramolecular structure a potential scaffolding for
use in molecular devices.
Previous preparations of the higher methylene homo-
logues of calixarenes are not general in scope and are
limited in the number of methylene units connecting the
aromatic rings. Additionally, their syntheses either re-
quire many steps to produce the macrocycle13 or produce
many macrocyclic products (individually in low yield)
necessitating extensive purification.14 For several years
we have labored to develop a more general and efficient
preparation of larger metacyclophanes and have com-
municated the synthesis of the endo-tetrahydroxy-
[3.3.3.3]metacyclophane (1)15 and the exo-tetrahydroxy-
[3.3.3.3]metacyclophane (2b),16 whose retrosynthetic analy-
sis is shown in Scheme 1. The macrocyclic synthesis uses
a common intermediate, bis-anisole 3a , for the prepara-
tion of both endo- and exo-metacyclophanes. Unlike the
synthesis1 of the parent metacyclophane, calix[4]arene,
no positional tert-butyl protecting group is needed during
the synthetic scheme due to the inherent regioselectivity
of organometallic coupling. We now report in full on a
general preparation of a family of exo-[n.m.n.m]meta-
cyclophanes, n,m g 3 (n ) m, or n * m), including an
exo-metacyclophane whose methylene bridges contain
ether functional groups, and detail the necessary modi-
fications to our earlier synthetic scheme that allow the
efficient preparation of exo-[n.m.n.m]metacyclophanes
where n,m > 3. Solution and solid-state characterization
F igu r e 1. Structures of exo-metacyclophanes. Numbering
system shown when n ) 3 and X ) CH2.
of the metacyclophanes are described, along with initial
results in the elaboration of the phenolic oxygens of exo-
metacyclophane 2b.
Resu lts a n d Discu ssion
Syn t h esis of exo-Tet r a m et h oxy[n .m .n .m ]m et a -
cyclop h a n es. The preparation of the family of exo-
[n.m.n.m]metacyclophanes 2 and 4-6 (Figure 1) was
made possible by the co-development of our soluble
copper catalyst, [CuBr-LiSPh-LiBr-THF].17 The Cu(I)
catalyst directs the high-yield coupling of 1 equiv of a
Grignard reagent with 1 equiv of an alkyl sulfonate and
is utilized in several steps of the exo-metacyclophane
synthetic scheme (Scheme 2). The Cu(I) catalyst is highly
reactive and proved to be much more efficient at coupling
the stabilized anisole Grignard reagent with the bis-
tosylate than other copper catalysts, such as Li2CuCl4
or CuBr/HMPA. Additionally, the coupling reaction is
effective when the Grignard reagent concentration is as
low as 0.05 M and the reaction temperature is 67 °C
(refluxing THF). These properties of our soluble copper
catalyst have enabled us to synthesize exo-metacyclo-
phanes 2a , 4, and 6 routinely in 40-70% yields, for
metacyclophane ring closure is promoted by elevated
(13) (a) Yamato, T.; Saruwatari, Y.; Yasumatsu, M. J . Chem. Soc.,
Perkin Trans. 1 1997, 1725-1730. (b) Yamato, T.; Matsumoto, J .;
Tokuhisa, K.; Kajihara, M.; Suehiro, K.; Tashiro, M. Chem. Ber. 1992,
125, 2443-2454. (c) Tashiro, M.; Tsuge, A.; Sawada, T.; Makishima,
T.; Horie, S.; Arimura, T.; Mataka, S.; Yamato, T. J . Org. Chem. 1990,
55, 2404-2409.
(14) (a) Schmitz, J .; Vo¨gtle, F.; Nieger, M.; Gloe, K.; Stephen, H.;
Heitsch, O.; Buschmann, H.-J . Supramol. Chem. 1994, 4, 115-119.
(b) Schmitz, J .; Vo¨gtle, F.; Nieger, M.; Gloe, K.; Stephen, H.; Heitsch,
O.; Buschmann, H.-J .; Hesse, W.; Cammann, K. C. Chem. Ber. 1993,
126, 2483-2491. (c) Vo¨gtle, F.; Schmitz, J .; Nieger, M. Chem. Ber. 1992,
125, 2523-2531.
(15) Burns, D. H.; Miller, J . D.; Santana, J . J . Org. Chem. 1993,
58, 6526-6528.
(16) Burns, D. H.; Miller, J . D. Tetrahedron Lett. 1994, 35, 5189-
5192.
(17) Burns, D. H.; Miller, J . D.; Chan, H.-K.; Delaney, M. O. J . Am.
Chem. Soc. 1997, 119, 2125-2133.

exo-[n.m.n.m]Metacyclophanes, n,m g 3
J . Org. Chem., Vol. 65, No. 17, 2000 5187
Sch em e 2
Sch em e 3
temperatures, and polymer byproduct is minimized when
the reaction is kept under concentrations < 0.1 M. The
oxygen-containing exo-metacyclophane 5 was synthesized
in 31% yield, but the lower yield was due primarily to
the difficulty in drying the more highly oxygenated
precursors 9c and 12c (as determined from IR spectros-
copy).
The synthetic pathway, detailed in Scheme 2, il-
lustrates a [2 + 2] approach to the construction of the
exo-[n.m.n.m]metacyclophane’s macrocyclic ring from two
bis-anisole precursors. The bis-anisole 3 was synthesized
in one step by Cu(I) catalyzed coupling of the Grignard
reagent, prepared from 2-bromoanisole, and an appropri-
ate bis-tosylate in 75-95% yield. Ring synthesis was
accomplished either in two additional steps, or with an
additional 5-step route that included the elaboration of
one of the bis-anisole precursors via a protection-depro-
tection sequence (compounds 9-12, 14, and 15). While
quick and easy, the overall 3-step exo-metacyclophane
synthesis (starting from 2-bromoanisole) worked poorly
when used to make the larger ring systems, primarily
due to the formation of large quantities of byproduct
[n.n]metacyclophane 16 (Scheme 3). For example, cyclo-
phane 2a was furnished in 40% yield when the bis-
Grignard of 9a and bis-tosylate 13a were allowed to react
under an inert atmosphere in the presence of 18 mol %
of the Cu(I) catalyst for 72 h. On the other hand, little of
the larger metacyclophanes 4 or 6 were produced by the
same procedure; rather, cyclophane 16 was produced in
the largest amount. An overall 6-step synthetic proce-
dure, again starting from 2-bromoanisole, proved more
fruitful by avoiding the difficulties associated with di-
functional reactants. Thus, elaboration of the bis-Grig-
nard of 9d via coupling (catalyzed by the Cu(I) catalyst)
with MOM-tosylate 15c, followed by deprotection and
tosylation, furnished the bis-tosylate 12d in 42% overall
yield. When the bis-Grignard of 9d and bis-tosylate 12d
were allowed to react under an inert atmosphere in the
presence of 18 mol % of the Cu(I) catalyst for 72 h,
metacyclophane 6 was furnished in 45% yield. Under the
same reaction conditions the bis-Grignard of 9a and bis-
tosylate 12a furnished the smaller metacyclophane 2a
routinely in 70% yield. In contrast, prior to the develop-
ment of our soluble copper catalyst and 6-step synthetic
scheme (that utilizes MOM-tosylates), we used the (com-
mon) catalyst system Cu(I)Br-HMPA to prepare exo-
metacyclophanes 7,8 from precursor bis-bromides 17a,17b

5188 J . Org. Chem., Vol. 65, No. 17, 2000
Burns et al.
Ta ble 1: Cr ysta llogr a p h ic Da ta
2a
Sch em e 4
6
formula
fw (g/mol)
cryst dimens (mm)
cryst syst
space group
cryst color
a, Å
C
40H48O4
C52H72O4
761.14
592.82
0.20 × 0.20 × 0.15
monoclinic
C2/c
colorless
31.930(9)
4.623(3)
28.232(7)
117.63(3)
3692(3)
4
1.066
room temp.
0.67
0.71069
0.085
0.080
0.60 × 0.50 × 0.25
monoclinic
P21/c
colorless
16.00(2)
8.850(3)
16.80(2)
105.81(9)
2289(4)
2
1.10
room temp.
0.67
0.71069
0.064
0.062
b, Å
c, Å
â, deg
V, Å3
Z
F
T, °C
calc, g/cm3
Sch em e 5
µ(Mo KR), cm-1
λ, Å
Ra (I > 2σ(I))
RWb(I > 2σ(I))
GOF
2.19
2.06
a
b
2 1/2
R )Σ||Fo| - |Fc||/Σ|Fo|. Rw ) [Σw(|F0| - |Fc|)2/ΣwFo
] .
calculations19 corroborate the flexibility of cyclophane 2a ,
indicating no real global minimum energy conformation
but rather several conformations with similar energy.
Presumably, the 1H NMR spectrum of 2a is a set of
averaged proton signals originating from several confor-
1
mations (vide infra). The H NMR spectra of the homolo-
gous metacyclophanes 4-8 exhibited similar aromatic,
methoxy, and methylene proton resonances and as a
group are conformationally mobile on the NMR time
scale. Cyclophane 2b16 was furnished in 92% yield when
cyclophane 2a was subjected to BBr3 in dichloromethane.
It was not possible to determine the existence of internal
hydrogen bonding between the phenolic hydrogens by 1H
NMR because 2b was only soluble in solvents such as
acetone or DMSO, but IR spectroscopy (KBr) exhibited
no detectable hydrogen bonding.16
Crystals of 2a and 6 suitable for X-ray crystallographic
analysis were grown by slow evaporation of a CH2Cl2
solution. The crystal data and refinement results for 2a
and 6 are presented in Table 1. The smaller parent exo-
calix[4]arene has been shown by X-ray crystallography
to exist in a cone conformation,18 and the crystal structure
likewise shows 2a to exist in a cone conformation (Figure
2). In contrast, the crystal structure of 6 is shown to
assume a chair conformation (Figure 3). Although the two
homologous metacyclophanes exhibit different conforma-
tions in the solid state, both cone and chair isomers have
very similar conformational energies (approximately 1.0
kcal/mol) for each metacyclophane as determined from
molecular mechanics calculations. Most likely these
conformations (and probably others) are in equilibrium
in solution.
in 23% yield or less (Scheme 4). Clearly the 6-step
synthetic scheme, in which three of the steps utilize our
Cu(I) catalyst as a coupling agent for Grignard and alkyl
sulfonate reagents, is an efficient and general preparation
of this family of exo-metacyclophanes. However, the
sensitivity of the Grignard reactions toward moisture
makes the preparation of exo-metacyclophane 5 (with a
more highly coordinating oxygen-containing bridge that
connects the anisole rings) more problematic than the
preparation of the all-methylene carbon analogue due to
the difficulty in drying the reactive tosylate precursors.
Solu tion a n d Solid -Sta te Str u ctu r e. The UV/vis
spectra of the exo-metacyclophanes are unremarkable.
1
The one methoxy resonance (3.75-3.79 ppm) in the H
NMR spectra of metacyclophanes 2a and 4-8 demon-
strates the symmetry of the macrocycles and indicates
their methoxy groups are not shielded by the aromatic
rings, i.e., they are directed outside of the rings, exhibit-
ing a normal anisole methoxy resonance (unlike endo-
metacyclophane 1, whose upfield methoxy resonance of
3.45 ppm suggests shielding from the aromatic rings15).
1
The H NMR spectrum of 2a at 323 K exhibits (besides
the one methoxy resonance) a doublet (4H) at 6.74 and
multiplet at 6.94-6.95 (8H) ppm in the aromatic region
and a somewhat broadened pair of triplet resonances at
2.53 and 2.67 ppm that correspond to the set of eight
ortho- and para-benzyl methylene protons. The straight-
forward proton resonances in the aromatic region, and
the triplets corresponding to methylene protons (which
demonstrates that equivalent methylene groups also
carry equivalent hydrogens), indicate the macrocycle is
conformationally mobile on the NMR time scale. That the
ring is conformationally mobile is not surprising since
the smaller exo-calix[4]arene ring is also conformationally
flexible.18 Indeed, the NMR spectra of 2a exhibits no
appreciable change in the appearance of its proton signals
over the temperature range 323-228 K. Force field
Molecule 2a crystallizes on a special position in the
monoclinic space group C2/c. A crystallographically im-
posed 2-fold axis extends through the center of the
molecule, perpendicular to the bowl. Molecule 6 crystal-
lizes on a special position in the monoclinic space group
P21/c, and the crystallographically imposed inversion
symmetry leads to the chair conformation. Both mol-
ecules’ bond angles and bond lengths are unexceptional.
(18) Bo¨hmer, V.; Do¨rrenba¨cher, R.; Frings, M.; Heydenreich, M.; de
Paoli, D.; Vogt, W.; Ferguson, G.; Thondorf, I. J . Org. Chem. 1996, 61,
549-559.
(19) CAChe 3.9 MM2, CAChe Scientific (Oxford Molecular), Bea-
verton, OR 97076.

exo-[n.m.n.m]Metacyclophanes, n,m g 3
J . Org. Chem., Vol. 65, No. 17, 2000 5189
creases in reactivity in the order PhOH > PhOR .
PhOCOR.1 Therefore, regiocontrol over the modification
of the phenolic oxygens is one way to control the elabora-
tion of the aromatic ring, which is desirable for the
controlled synthesis of more complex nanostructures of
defined function. The exo-tetrahydroxymetacyclophanes
contain two possible orientations of adjacent phenolic
oxygens with respect to one another; either with a para
or ortho connection via the methylenes that bridge two
phenol rings. Accordingly, three (1,2-para, 1,2-ortho, and
1,3) possible di-O-substituted isomers can form upon the
alkylation or acylation of the phenolic oxygens, as well
as the mono-, tri-, and tetra-O-substituted isomers.
Regiocontrol over such elaboration, starting from exo-
tetrahydroxymetacyclophanes of various size, would seem
a daunting task. Considering the stepwise approach to
the design of the ring system, it may ultimately prove
best to instead use several different “directed ortho
metalation” functional groups that can be selectively
unmasked to furnish a desired pattern of free phenols.
As a starting point, however, we examined the acylation
and alkylation of the exo-tetrahydroxy[3.3.3.3]meta-
cyclophane 2b.
F igu r e 2. ORTEP diagram illustrating the cone conformation
of 2a (a disordered solvent molecule of water found in the
cavity and hydrogens are omitted for reasons of clarity); 50%
probability ellipsoids are displayed.
Acylation of 2b with acetyl chloride in THF and Et3N
at room temperature or below led to all possible substi-
tuted isomers, although the mono-, di-, tri-, and tetra-
O-acylated isomers could be separated with chromatog-
raphy. Only when 2b and excess acetyl chloride were
allowed to stir at reflux for 24 h did one isomer predomi-
nate, the tetra-O-acylated isomer, furnished in 85% yield
along with small amounts of easily separated mono-, di-
and tri-O-acylated isomers. Besides the experimental
evidence cited above, structural properties intrinsic to the
ring indicate there would be difficulty in the regioselec-
tive preparation of isomers other than the tetra-O-
substituted isomer. CPK model analysis predicts that any
attempt to use steric interactions between adjacent
phenolic oxygen substituents (as can be done in calix[4]-
arene chemistry1) to direct acetylation or alkylation in a
regioselective manner would most likely fail because of
the large distance (approximately 9-13 Å) that separates
F igu r e 3. ORTEP diagram illustrating the chair conformation
of 6 (hydrogens are omitted for reasons of clarity); 50%
probability ellipsoids are displayed.
The inclination of the phenyl rings to the mean plane of
the molecule (defined as the plane that contains the four
benzyl methylene carbons either para or ortho to the
methoxy group) is 41-42° for 2a in the cone conforma-
tion. In the chair conformation of 6 one pair of diagonally
placed phenyl rings is inclined 60-70° above or below
the plane of the other pair, and each pair of parallel
methylene bridges is roughly perpendicular to the other.20
Perhaps the most intriguing structural feature common
to both the exo-metacyclophanes is their large size. The
distance between phenyl rings diagonal to each other in
the cone conformation of 2a is 8.6-8.7 Å and in the chair
conformation of 6 is 11.9-13.0 Å (calculated distance
between two carbons, each occupying a position between
the two methylene bridges in a set of diagonal phenol
rings).
1
the phenolic oxygens. Furthermore, the IR and H NMR
spectra of 2b exhibit no intramolecular hydrogen bonding
between phenols (vide supra). Any preferential formation
of the three possible dianions (1,2-ortho, 1,2-para, or 1,3)
due to stabilization via intramolecular hydrogen bonding,
and therefore consequent regiocontrol of alkylation or
acylation would seem unlikely.
Rather than address the above issues by experimenting
further with larger acyl chlorides or different bases, we
shifted our attention to the use of difunctional electro-
philes in the expectation that fewer regioisomers would
result from this type of modification to the exo-metacy-
clophane’s phenolic oxygens. It seemed probable that 1
equiv of a small electrophile such as bromochloromethane
might preferentially react with adjacent phenolic oxygens
in a 1,2-ortho pattern since semiempirical calculations21
showed that the heat of formation of the 1,2-ortho adduct
19a (Figure 4) was 6 kcal more stable than the 1,3 adduct
19b and that the 1,2-para adduct would be too high in
energy to form. Reaction of 2b with 1 equiv of bromo-
chloromethane in DMSO and K2CO3 furnished a mono-
adduct in 63% purified yield. Due to the low boiling point
P h en olic Oxygen Mod ifica tion . The reactivity to-
ward aromatic electrophilic substitution of the unsub-
stituted ortho-positions on the exo-metacyclophane’s
aromatic rings is dependent upon the nature of the
substituent on the phenolic oxygen, i.e., the ring de-
(20) The conformation of 6 allows the molecules to pack in an
alternating fashion such that each cyclophane has a neighboring
cyclophane above it and another below it with one methoxy group from
each of the neighboring cyclophanes directed into the center of the
cyclophane ring.
(21) CAChe 3.9 MOPAC/PM3 (J ames Stewart), CAChe Scientific
(Oxford Molecular), Beaverton, OR 97076.

5190 J . Org. Chem., Vol. 65, No. 17, 2000
Burns et al.
F igu r e 5. Minimized (PM3) structures of bis(methylene-
linked) 20 (hydrogens are omitted for reasons of clarity). Top:
cone conformation 20a . Bottom: 1,2-alternate conformation
20b.
the para-benzyl protons, leading to the expectation that
two triplet proton resonances, each corresponding to 8
protons, would be observed in its spectrum. More diag-
nostic, however, is the aromatic region in the mono-
adduct’s spectrum, which contains proton resonances
nearly identical to those observed in the spectrum of 2b.
CPK model analysis indicates that, starting with the
PM3 optimized structure of 19b, it would take only very
small phenol ring rotations to place the phenol’s meta-
proton on top of the π-system of an adjacent phenol ring.
Each of these meta-protons should be shielded by the
adjacent aromatic ring, and their resonances shifted
upfield in comparison to those of 2b. Since this type of
aromatic ring shielding would not occur in 19a , the
upfield resonance shifts would not be expected to be
F igu r e 4. Minimized (PM3) structures of mono(methylene-
linked) 19. Top: 1,2-adduct 10a . Bottom: 1,3-adduct 19b.
of bromochloromethane, the reaction temperature was
kept at 60 °C overnight, allowing the alkylation of one
phenolic oxygen. The temperature was then raised to 120
°C, and the reaction mixture allowed to stir for an
additional 48 h to complete the ring formation. While
attempts to prepare a bis-adduct directly from 2b proved
problematic, the bis-adduct was furnished in 54% yield
by reaction of the monoadduct 19 with bromochloro-
methane using the procedure discussed above.
1
present in its H NMR spectrum. Thus, exo-metacyclo-
phane 19a would seem the more likely structure of the
two monoadducts, given its more stable calculated heat
of formation and that the aromatic region in the mono-
1
1
Whereas the H NMR spectrum of 2b exhibits a pair
adducts H NMR spectrum is so similar to that of 2b.
of triplet resonances for the ortho and para-benzyl
methylene protons (8H at 2.53 ppm and 8H at 2.67 ppm),
the H NMR spectrum of the monoadduct exhibits three
An exo-metacyclophane with both sets of ortho-phenolic
oxygens bridged by a methylene carbon is consistent with
the spectral analysis of the bis-adduct prepared from 19a .
As in the case with the cone and 1,2-alternate conforma-
tion of the bis(methylene-linked) exo-calix[4]arene re-
ported by Sorrel,22 it is not possible to distinguish
between the cone conformation of 20a (Figure 5) and 1,2-
1
triplets (8H at 2.50 ppm, 4H at 2.63 ppm, and 4H at 2.84
ppm). This spectrum is consistent with the optimized
geometry of monoadduct 19a , where the ortho-benzyl
protons that occupy positions in the newly formed ring
experience a different electronic environment from that
of the ortho-benzyl protons associated with the remaining
phenols (the 8 para-benzyl protons experience very
similar electronic environments and it is not surprising
1
alternate conformation of 20b by their H NMR spectra
due to symmetry considerations. The NMR spectra of 20
exhibits only slight broadening of its protons signals over
the temperature range 323-228 K (the largest change
is seen in the triplets at 2.54 and 2.72 ppm, which
coalesce into two broad singlets by 312 K). While this
suggest 20 is less flexible than 2a , it also shows that the
bis(methylene-linked) adduct is also conformationally
mobile on the NMR time scale like its parent exo-
1
that the H NMR spectrum would exhibit only the one
corresponding triplet). Examination of the optimized
structure of 19b shows that it contains a C2 axis which
cuts through the center of the molecule perpendicular to
the methylene attached to the two phenol oxygens. In
this structure, the ortho-benzyl methylene protons prob-
ably experience similar electronic environments, as do
(22) Sorrell, T. N.; Yuan, H. J . Org. Chem. 1997, 62, 1899-1902.

exo-[n.m.n.m]Metacyclophanes, n,m g 3
J . Org. Chem., Vol. 65, No. 17, 2000 5191
metacyclophane. The simple rt 1H NMR spectrum and
narrow melting point range of the bis-adduct 20 suggests
it is likely one compound. Both molecular mechanics and
semiempirical calculations show the two conformations
20a and 20b, which cannot interconvert into one another,
are less than 1 kcal/mol apart in energy. Accordingly,
absolute proof of the structure for both 19 and 20 will
have to wait for the preparation of suitable crystals for
X-ray diffraction.
Str u ctu r e Deter m in a tion s. The crystal structures for exo-
tetramethoxy[3.3.3.3]metacyclophane (2a ) and exo-tetra-
methoxy[6.6.6.6]metacyclophane (6) were performed at room
temperature using graphite-monochromated Mo KR radiation
on an Enraf-Nonius CAD4 diffractometer controlled by soft-
ware running on an SGI O2 computer. The crystals were
affixed with epoxy to the tip of a glass fiber which was mounted
in the gonoiometer head on the diffractometer. The unit cells
were determined from the setting angles of 24 reflections with
20° < 2θ < 24° and confirmed by axial photographs. For 2a ,
2797 reflections were collected (ω - 2θ; +h, +k, (l; 2° e 2θ e
45°), giving a unique set of 2758 reflections (Rint ) 0.139) and
1186 observed reflections (I > 1σ(I)). For 6, 3366 reflections
were collected (ω; +h, +k, (l; 2° e 2θ e 45°), giving a unique
set of 3242 reflections (Rint ) 0.039) and 1721 observed
reflections (I > 2σ(I)). The data were processed, and the
structures were solved and refined using the TeXsan pack-
age.26 The data were corrected for Lorentz and polarization
effects, an empirical absorption correction based on azimuthal
scans of three intense reflections (transmission factors: 2a ;
0.9314-0.9910, 6; 0.8840-0.9997), and secondary extinction
(2a , 2.01212 × 10-7; 6, 1.03788 × 10-6). No decay was detected
by measurement of three intense reflections. The structures
were solved by direct methods27 and refined by full-matrix
least-squares techniques with values for ∆f ′ and ∆f ′′ from
Creagh and McAuley.28 The structure of 2a includes extra
electron density in the center of the molecule corresponding
to a disordered solvent, which was modeled with three partially
occupied oxygen atoms representing a disordered water of
crystallization. These atoms were included with isotropic
thermal parameters. All other non-hydrogen atoms were
refined with anisotropic temperature factors, and the attached
hydrogen atoms were included at idealized positions but were
not refined. Pertinent details are given in Table 1.
Gen er a l P r oced u r e for th e P r ep a r a tion of bis-An i-
sole: 1,1′-(1,3-P r op a n ed iyl)bis[2-m eth oxyben zen e] (3a ).
THF (160 mL) was added to magnesium turnings (10.84 g,
446 mmol), and the reaction mixture was heated to reflux. A
solution of 2-bromoanisole (16.69 g, 89.2 mmol) in THF (18
mL) was added via syringe at a rate of 0.6 mL/min to the
reaction mixture. The resulting Grignard reaction was allowed
to stir at reflux for 20 h and then cooled to room temperature.
A second solution consisting of 1,3-propanediol, bis(4-methyl-
benzenesulfonate) (13a ) (17.15 g, 44.6 mmol) in THF (20 mL),
26.8 mL (6 mol %) of 0.1 M (LiBr/CuBr‚SMe2/LiSPh/THF)
copper catalyst solution, and HMPA (11.4 mL; 6% v/v based
on the volume of the Grignard reaction) was heated to reflux.
The cooled Grignard solution, decanted from excess magne-
sium, was then added to the refluxing reaction mixture with
a cannulating needle. After 2 h, an additional 13.4 mL (3 mol
%) of 0.1 M (LiBr/CuBr‚SMe2/LiSPh/THF) copper catalyst
solution was added, and the reaction mixture was stirred at
reflux for an additional 20 h. The reaction was then cooled to
room temperature, quenched with 1.5 M HCl (150 mL), and
extracted with CH2Cl2 (4 × 50 mL). The combined organic
layers were washed with another portion of 1.5 M HCl (150
mL), followed by brine (150 mL), dried over Na2SO4, and
concentrated under vacuum to yield off-white crystals. Re-
crystallization from ethanol yielded 10.95 g of the title
compound (42.9 mmol, 96%) as white crystals: mp 53-54 °C;
1H NMR δ 1.86-1.95 (m, 2H), 2.67 (t, 4H, J ) 7.83 Hz), 3.80
(s, 6H), 6.80-6.91 (m, 4H), 7.10-7.23 (m, 4H); 13C NMR (100.5
MHz) δ 29.67, 30.08, 55.26, 110.26, 120.30, 126.76, 129.67,
131.11, 157.54; HRMS m/z calcd for 256.1463, found 256.1461.
Anal. Calcd for C17H20O2: C, 79.65; H, 7.86. Found: C, 79.53;
H, 8.01.
Con clu sion
The general preparation of exo-tetramethoxy[n.m.n.m]-
metacyclophanes in good to moderate yield is possible via
a 6-step synthetic strategy that relies heavily on our
soluble copper catalyst [CuBr-LiSPh-LiBr-THF] to
efficiently couple Grignard and alkyl tosylate reagents.
The exo-metacyclophane rings are flexible on the NMR
time scale, and molecular mechanics calculations indicate
the cone and chair conformations seen in the crystal
structures of 2a and 6 have very similar energies and
are therefore most likely in equilibrium in solution.
Regiocontrol over the alkylation and acylation of the
phenolic oxygens of 2b is problematic, although the
preparation of the tetra-acylated 18, and alkylated 19
and 20 is straightforward.
Exp er im en ta l Section
Ma ter ia ls a n d P r oced u r es. The following chemicals were
obtained commercially and dried and/or purified according to
literature procedures before use23 (all solvents were dried
unless otherwise noted): tetrahydrofuran (THF) and diethyl
ether (Et2O) were distilled from sodium and benzophenone;
tetramethylethylenediamine (TMED), pyridine, and dimethoxy-
methane (MOM) were distilled from sodium; hexamethylphos-
phoramide (HMPA) was distilled from sodium under high
vacuum; 2-bromoanisole was distilled from calcium hydride
under vacuum; 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol,
and diethylene glycol were dried over sodium carbonate,
filtered, and then fractionally distilled; 1,2-dichloroethane was
predried over CaCl2 and then distilled from P2O5; chloroform
and CH2Cl2 were distilled from P2O5. Lithium bromide, cu-
prous bromide-dimethyl sulfide, para-toluenesulfonyl chlo-
ride, (dimethylamino)pyridine (DMAP), and 1,3-propanediol
di-para-tosylate were used as received from Aldrich Chemical
Co. Lithium reagents were assayed according to literature
procedures.24 All reactions were performed under a nitrogen
atmosphere obtained by passing the nitrogen through a drying
tower containing 3 Å molecular sieves, or were performed in
a Vacuum Atmospheres glovebox under a nitrogen atmo-
sphere.
All melting points (Mel-Temp) and boiling points (micro
boiling point apparatus) are uncorrected. 1H NMR spectra were
recorded at either 400 or 300 MHz in CDCl3 with Me4Si as an
internal reference unless otherwise specified. Low-resolution
mass spectra were obtained at 70 eV using a Finnigan INCOS
50 direct inlet system, and HRMS were obtained on a VG ZAB
system. Column chromatography was carried out on silica gel
(Davisil 633), and analytical thin-layer chromatography was
performed using precoated Analtech Uniplates (silica gel GF).
Samples that were used for spectral and analytical analyses
were purified by radial chromatography using a Chroma-
totron.25 Analytical samples were dried under vacuum in a
drying pistol at 120 °C for a minimum of 2 days. Elemental
analysis was done by Desert Analytics, Tucson, AZ.
1,1′-(1,4-Bu ta n ed iyl)bis[2-m eth oxyben zen e] (3b). The
reaction of a Grignard solution, made from magnesium turn-
(26) TeXsan: Crystal Structure Analysis Package, Molecular Struc-
ture Corporation (1985 and 1992).
(23) Perrin, D.: Armarego, W. Purification of Laboratory Chemicals;
Pergamon Press: New York, 1988.
(24) (a) Watson, S.: Eastham, J . J . Organomet. Chem. 1967, 9, 165-
168. (b) Kofron, W.; Baclawski, L. J . Org. Chem., 1976, 41, 1879-1890.
(25) Harrison Research, 840 Moana Court, Palo Alto, CA.
(27) SIR92: Altomare, A.; Cascarano, M.; Giacovazzo, C.; Guagliardi,
A. J . Appl. Crystallogr. 1993, 26, 343.
(28) Creagh, D. C.; McAuley, W. J . International Tables for Crystal-
lography, Vol. C; Wilson, A. J . C., Ed.; Kluwer Academic Publishers:
Boston, MA, 1992.

5192 J . Org. Chem., Vol. 65, No. 17, 2000
Burns et al.
ings (1.28 g, 52.7 mmol) and 2-bromoanisole (0.98 g, 5.26
mmol) in THF (10.5 mL), and a refluxing solution consisting
of 1,4-butanediol, bis(4-methylbenzenesulfonate) (13b) (1.05
g, 2.63 mmol) in THF (6.7 mL), HMPA (1.8 mL), and a total
of 6.6 mL of 0.1 M LiBr/CuBr‚SMe2/LiSPh/THF furnished 0.66
g of the title compound (2.44 mmol, 93%) as white crystals
7.88 g (17.8 mmol, 89.2%) of the title compound as white
crystals after recrystallization from ethanol: mp 114-116 °C;
1H NMR δ 2.59 (t, 4H, J ) 7.92 Hz), 3.45-3.54 (m, 4H), 3.77
(s, 6H), 6.74-6.79 (m, 2H), 7.37-7.42 (m, 4H); 13C NMR (100.5
MHz) δ 34.28, 57.05, 66.81, 112.23, 114.17, 129.82, 133.62,
134.29, 159.73. LRMS m/z 443 (M+), 364, 286, 257, 229, 213,
178, 91. Anal. Calcd for C18H20Br2O3: C, 48.68; H, 4.54.
Found: C, 48.39; H, 4.61.
1
after recrystallization from ethanol: mp 65-66 °C; H NMR
δ 1.61-1.68 (m, 4H), 2.52-2.68 (m, 4H), 3.80 (s, 6H), 6.81-
6.89 (m, 4H), 7.09-7.19 (m, 4H); 13C NMR (100.5 MHz) δ 29.71,
29.96, 55.27, 110.26, 120.29, 126.72, 129.79, 131.26, 157.48;
LRMS m/z 270 (M+), 254, 163, 91. Anal. Calcd for C18H22O2:
C, 79.96; H, 8.20. Found: C, 79.73; H, 8.21.
1,1′-(1,6-Hexa n ed iyl)bis[5-b r om o-2-m et h oxyb en zen e]
(9d ). The reaction of 1,1′-(1,6-hexanediyl)bis[2-methoxyben-
zene] (3d ) (5.47 g, 18.3 mmol) and bromine (5.86 mL, 73.4
mmol) in CHCl3 (20.5 mL) furnished 7.82 g (17.2 mmol, 93.9%)
of the title compound as white crystals after recrystallization
1,1′-(1,1′-(2,2′-Oxyb iset h a n e)d iyl)b is[2-m et h oxyb en -
zen e] (3c). The reaction of a Grignard solution, made from
magnesium turnings (1.87 g, 76.9 mmol) and 2-bromoanisole
(1.43 g, 7.69 mmol) in THF (15.4 mL), and a refluxing solution
consisting of 1,1′-(2,2′-oxybisethanol), bis(4-methylbenzene-
sulfonate) 13c (1.59 g, 3.85 mmol) dissolved in THF (9.7 mL),
HMPA (1.0 mL), and a total of 6.9 mL of 0.1 M LiBr/CuBr‚
SMe2/LiSPh/THF furnished 1.03 g of the title compound (3.58
mmol, 93%) as white crystals after recrystallization from
ethanol: mp 98-99 °C; 1H NMR δ 2.65 (t, 4H, J ) 7.92), 3.52-
3.59 (m, 4H), 3.79 (s, 6H), 6.87-6.99 (m, 4H), 7.23-7.38 (m,
4H); 13C NMR (100.5 MHz) δ 34.92, 56.83, 66.36, 110.63,
121.84, 128.01, 130.91, 132.25, 158.87; LRMS m/z 286 (M+),
178, 151, 91. Anal. Calcd for C18H22O3: C, 75.50; H, 7.74.
Found: C, 75.17; H, 8.06.
1
from ethanol: mp 86-88 °C; H NMR δ 1.31-1.41 (m, 4H),
1.49-1.63 (m, 4H), 2.56 (t, 4H, J ) 7.9 Hz), 3.82 (s, 6H), 6.69
(d, 2H, J ) 8.0 Hz), 7.22-7.26 (m, 4H); 13C NMR (100.5 MHz)
δ 28.86, 30.32, 30.68, 55.49, 111.86, 112.74, 129.42, 132.37,
133.36, 158.35; LRMS m/z 456 (M+), 377, 297, 271, 185, 91.
Anal. Calcd for C20H24Br2O2: C, 52.65; H, 5.30. Found: C,
52.67; H, 5.41.
Gen er a l P r oced u r e for th e P r ep a r a tion of MOM-
P r ot ect ed b is-An isole: 1,1′-(1,3-P r op a n ed iyl)b is[5-(3-
m eth oxym eth oxyp r op yl)-2-m eth oxyben zen e] (10a ). THF
(3 mL) was added to magnesium turnings (0.783 g, 32.2 mmol),
and the reaction mixture was heated to reflux. The bis-anisole
9a (1.33 g, 3.22 mmol) was dissolved in THF (3.4 mL) and
transferred into the refluxing reaction mixture via syringe at
a rate of 0.12 mL/min. The resulting Grignard solution was
stirred at reflux for 20 h and then cooled to room temperature.
A second solution consisting of MOM-protected tosylate 15a
(5.29 g, 19.3 mmol) dissolved in THF (2.2 mL), 3.8 mL (12 mol
%) of 0.1 M (LiBr/CuBr‚SMe2/LiSPh/ THF) copper catalyst
solution, and HMPA (0.41 mL; 6% v/v based on the volume of
the Grignard reaction) was heated to reflux. The cooled
Grignard solution, decanted from excess magnesium, was then
added to the refluxing reaction mixture with a cannulating
needle. After 2 h, an additional 1.9 mL (6 mol %) of 0.1 M
LiBr/CuBr‚SMe2/LiSPh/THF was added. The reaction mixture
was stirred at reflux for an additional 20 h, cooled to room
temperature, quenched with 1.5 M HCl (50 mL), and extracted
with CH2Cl2 (4 × 30 mL). The combined organic layers were
washed with another portion of 1.5 M HCl (50 mL), followed
by brine (50 mL), dried over Na2SO4, and concentrated under
vacuum to yield a yellowish oil. The crude product was purified
by silica gel column chromatography (90:10 hexane/ethyl
acetate) to yield 1.42 g (2.41 mmol, 75%) of the title compound
1,1′-(1,6-Hexa n ed iyl)bis[2-m eth oxyben zen e] (3d ). The
reaction of a Grignard solution, made from magnesium turn-
ings (1.00 g, 41.1 mmol) and 2-bromoanisole (0.76 g, 4.11
mmol) in THF (8.2 mL), and a refluxing solution consisting of
1,6-hexanediol, bis(4-methylbenzenesulfonate) 13d (0.88 g,
2.06 mmol) dissolved in THF (5.4 mL), HMPA (0.5 mL), and a
total of 2.4 mL of 0.1 M LiBr/CuBr‚SMe2/LiSPh/THF furnished
0.45 g (1.5 mmol, 73%) of the title compound as white crystals
1
after recrystallization from ethanol: mp 70-71 °C; H NMR
δ 1.35-1.42 (m, 4H), 1.51-1.65 (m, 4H), 2.57 (t, 4H, J ) 7.8
Hz), 3.85 (s, 6H), 6.81-6.90 (m, 4H), 7.10-7.19 (m, 4H); 13C
NMR (100.5 MHz) δ 29.49, 29.85, 30.13, 55.23, 110.26, 120.30,
126.70, 129.72, 131.39, 157.47; LRMS m/z 298 (M+), 191, 107,
91. Anal. Calcd for C20H26O2: C, 80.50; H, 8.78. Found: C,
80.60; H, 8.77.
Gen er a l P r oced u r e for th e P r ep a r a tion of 5,5′-Di-
br om o-bis-a n isole: 1,1′-(1,3-P r op a n ed iyl)bis[5-br om o-2-
m eth oxyben zen e] (9a ). Bis-anisole 3a (3.08 g, 12.0 mmol)
was dissolved in CHCl3 (13.4 mL), the solution was cooled to
0 °C on an ice-water bath, and bromine (1.24 g, 48.06 mmol)
was added dropwise (CHCl3 with ethanol inhibitor was used
directly from the bottle; HBr gas produced in the reaction was
collected in two KOH traps cooled on dry ice/acetone baths).
The reaction was stirred an additional 2 h, quenched with 1.5
M HCl (100 mL), extracted with Et2O (3 × 50 mL), washed
with brine (100 mL), and concentrated under vacuum. The
crude solid was recrystallized from ethanol to yield 4.97 g
(11.99 mmol, 99.9%) of the title compound as white crystals:
1
as a clear oil: bp 125-126 °C; H NMR δ 1.83-1.92 (m, 6H),
2.62-2.70 (m, 8H), 3.28 (s, 6H), 3.64-3.72 (m, 4H), 3.82 (s,
6H), 4.69 (s, 4H), 6.73 (d, 2H, J ) 7.5 Hz), 6.91-7.02 (m, 4H);
13C NMR (100.5 MHz) δ 30.85, 32.82, 33.62, 54.86, 56.31, 68.95,
99.07, 111.63, 127.97, 128.65, 130.74, 133.98, 154.89; LRMS
m/z 460 (M+), 416, 370, 359, 256, 91. Anal. Calcd for
C
27H40O6: C, 70.41; H, 8.75. Found: C, 70.34; H, 8.82.
1,1′-(1,4-Bu ta n ed iyl)bis[5-(4-m eth oxym eth oxybu tyl)-2-
m eth oxyben zen e] (10b). The reaction of a Grignard solution,
made from magnesium turnings (2.06 g, 84.7 mmol) and bis-
anisole 9b (3.61 g, 8.47 mmol) in THF (15 mL), and a refluxing
solution consisting of MOM-protected tosylate 15b (13.08 g,
45.4 mmol) dissolved in THF (5.2 mL), HMPA (0.96 mL), and
a total of 13.4 mL of 0.1 M (LiBr/CuBr‚SMe2/LiSPh/THF)
copper catalyst solution furnished, after purification by silica
gel column chromatography (90:10 hexane/ethyl acetate), 2.49
g (5.08 mmol, 60%) of the title compound as a clear oil: bp
188-190 °C; 1H NMR δ 1.56-1.89 (m, 12H), 2.57-2.71 (m,
8H), 3.26 (s, 6H), 3.62-3.74 (m, 4H), 3.79 (s, 6H), 4.71 (s, 4H),
6.78 (d, 2H, J ) 7.5 Hz), 6.87-6.97 (m, 4H); 13C NMR (100.5
MHz) δ 30.85, 32.82, 33.05, 33.62, 54.86, 56.31, 68.95, 99.07,
111.63, 127.97, 128.65, 130.74, 133.98, 154.89; LRMS m/z 502
(M+), 458, 412, 401, 256, 91. Anal. Calcd for C30H46O6: C,
71.68; H, 9.22. Found: C, 71.83; H, 9.49.
1
mp 60-61 °C; H NMR δ 1.79-1.90 (m, 2H), 2.61 (t, 4H, J )
7.7 Hz), 3.79 (s, 6H), 6.67-6.70 (m, 2H), 7.24-7.26 (m, 4H);
13C NMR (100.5 MHz) δ 29.04, 29.62, 55.51, 111.87, 112.57,
129.46, 132.31, 133.09, 156.65; HRMS m/z calcd for C17H18
-
Br2O2 411.9676, found 411.9674. Anal. Calcd for C17H18Br2O2:
C, 49.30; H, 4.39. Found: C, 49.43; H, 4.26.
1,1′-(1,4-Bu t a n ed iyl)b is[5-b r om o-2-m et h oxyb en zen e]
(9b). The reaction of 1,1′-(1,4-butanediyl)bis[2-methoxyben-
zene] (3b) (4.27 g, 15.8 mmol) and bromine (1.63 g, 63.3 mmol)
in CHCl3 (17.6 mL) furnished 6.56 g (15.4 mmol, 97.5%) of
the title compound as white crystals after recrystallization
1
from ethanol: mp 78-79 °C; H NMR δ 1.55-1.61 (m, 4H),
2.46-2.62 (m, 4H), 3.78 (s, 6H), 6.68-6.76 (m, 4H), 7.23-7.26
(m, 2H); 13C NMR (100.5 MHz) δ 29.11, 29.56, 55.52, 111.87,
112.86, 129.22, 130.99, 133.16, 156.53; LRMS m/z 427 (M+),
348, 269, 91. Anal. Calcd for C18H20Br2O2: C, 50.49; H, 4.71.
Found: C, 50.61; H, 4.43.
1,1′-(1,1′-(2,2′-Oxyb ise t h a n e )d iyl)b is[5-(3-m e t h oxy-
m eth oxyp r op yl)-2-m eth oxyben zen e] (10c). The reaction of
a Grignard solution, made from magnesium turnings (1.84 g,
75.7 mmol) and bis-anisole 9c (3.40 g, 7.57 mmol) in THF (17
mL), and a refluxing solution consisting of MOM-protected
1,1′-(1,1′-(2,2′-Oxybiseth a n e)d iyl)bis[5-br om o-2-m eth -
oxyben zen e] (9c). The reaction of 3c (5.72 g, 20.0 mmol) and
bromine (6.39 mL, 80.0 mmol) in CHCl3 (22.3 mL) furnished

exo-[n.m.n.m]Metacyclophanes, n,m g 3
J . Org. Chem., Vol. 65, No. 17, 2000 5193
tosylate 15a (13.92 g, 50.8 mmol) dissolved in THF (5.9 mL),
HMPA (1.1 mL), and a total of 13.6 mL of 0.1 M (LiBr/CuBr‚
SMe2/LiSPh/THF) copper catalyst solution furnished, after
purification by silica gel column chromatography (90:10 hex-
ane/ethyl acetate), 2.94 g (5.84 mmol, 69%) of the title
compound as a clear oil: bp 139-141 °C; 1H NMR δ 1.83-
1.92 (m, 4H), 2.65 (t, 8H, J ) 7.92 Hz), 3.28 (s, 6H), 3.52-
3.59 (m, 4H), 3.64-3.72 (m, 4H), 3.79 (s, 6H), 4.69 (s, 4H), 6.73
(d, 2H, J ) 7.5 Hz), 6.91-7.02 (m, 4H); 13C NMR (100.5 MHz)
δ 32.39, 34.65, 55.9, 56.71, 67.56, 69.17, 97.86, 110.57, 121.62,
127.60, 131.46, 132.75, 158.52; LRMS m/z 490 (M+), 445, 400,
386, 341, 286, 253, 91. Anal. Calcd for C28H42O7: C, 68.55; H,
8.63. Found: C, 68.29; H, 8.99.
1,1′-(1,6-Hexa n ed iyl)bis[5-(6-m eth oxym eth oxyh exyl)-
2-m eth oxyben zen e] (10d ). The reaction of a Grignard solu-
tion, made from magnesium turnings (1.79 g, 73.8 mmol) and
bis-anisole 9d (3.35 g, 7.38 mmol) in THF (15 mL), and a
refluxing solution consisting of MOM-protected tosylate 15c
(14.0 g, 44.3 mmol) dissolved in THF (5.1 mL), HMPA (0.94
mL), and a total of 13.2 mL of 0.1 M (LiBr/CuBr‚SMe2/LiSPh/
THF) copper catalyst solution furnished, after purification by
silica gel column chromatography (90:10 hexane/ethyl acetate),
3.16 g (5.39 mmol, 73%) of the title compound as a clear oil:
bp 149-151 °C; 1H NMR δ 1.31-1.44 (m, 12H), 1.50-1.67 (m,
12H), 2.48-2.61 (m, 8H), 3.36 (s, 6H), 3.52 (t, 4H, J ) 11.7
Hz), 3.79 (s, 6H), 4.61 (s, 4H), 6.75 (d, 2H, J ) 9.0 Hz), 6.94
(d, 4H, J ) 10.5 Hz); 13C NMR (100.5 MHz) δ 26.10, 29.11,
29.56, 29.69, 30.0, 30.24, 31.71, 55.07, 55.39, 67.84, 96.40,
110.14, 126.20, 129.88, 131.12, 134.45, 155.53; LRMS m/z 586
(M+), 541, 496, 441, 335, 297, 271, 251, 91. Anal. Calcd for
7.00 (m, 4H); 13C NMR (100.5 MHz) δ 31.54, 34.39, 55.62,
67.81, 69.41, 111.07, 121.70, 127.34, 131.86, 132.73, 157.29;
LRMS m/z 402 (M+), 342, 286, 22, 209, 193, 91. Anal. Calcd
for C24H34O5: C, 71.61; H, 8.51. Found: C, 71.46; H, 8.63.
1,1′-(1,6-Hexan ediyl)bis[5-(6-h ydr oxyh exyl)-2-m eth oxy-
ben zen e] (11d ). The reaction of MOM-protected bis-anisole
10d (5.10 g, 8.69 mmol) in methanol (43 mL) and 12 M HCl (2
mL, 24 mmol) furnished 4.25 g (8.52 mmol, 98%) of the title
compound as white crystals after recrystallization from etha-
nol: mp 62-64 °C; 1H NMR δ 1.34-1.45 (m, 14H), 1.52-1.69
(m, 12H), 2.48-2.60 (m, 8H), 3.61 (t, 4H, J ) 9.0 Hz), 3.78 (s,
6H), 6.74 (d, 2H, J ) 10.5 Hz), 6.90 (d, 4H, J ) 10.5 Hz); 13C
NMR (100.5 MHz) δ 26.13, 29.12, 29.55, 29.72, 29.99, 30.26,
31.73, 55.06, 67.85, 110.16, 126.21, 129.89, 131.11, 134.47,
155.52; LRMS m/z 498 (M+), 397, 297, 291, 207, 91. Anal. Calcd
for C32H50O4: C, 77.06; H, 10.10. Found: C, 76.69; H, 10.31.
Gen er a l P r oced u r e for th e P r ep a r a tion of bis-Tosyl-
a te-bis-a n isole: 1,1′-(1,3-P r op a n ed iyl)bis[5-(3-(4-m eth yl-
ben zen esu lfon yloxy)p r op yl)-2-m eth oxyben zen e] (12a ). A
solution of bis-anisole 11a (1.85 g, 4.97 mmol) in CH2Cl2 (10
mL) and pyridine (3.22 mL, 39.8 mmol) was allowed to cool to
0 °C. p-Toluenesulfonyl chloride (2.82 g, 15.0 mmol) was added
slowly over 5 min, and the reaction mixture was allowed to
stir for 20 h and then quenched with 3 M HCl (100 mL). The
resulting solution was extracted with CH2Cl2 (3 × 100 mL),
and the organic layers were combined, dried over Na2SO4, and
concentrated under vacuum. The crude product was purified
by silica gel (plug) column chromatography (75:25 hexane/ethyl
acetate) to yield 3.28 g (4.82 mmol, 97%) of the title compound
1
as a clear oil: bp 143-144 °C; H NMR δ 1.74-1.95 (m, 6H),
C
36H58O6: C, 73.68; H, 9.96. Found: C, 73.71; H, 9.78.
2.44 (s, 6H), 2.59-2.68 (m, 8H), 3.82 (s, 6H), 4.03 (t, 4H, J )
13.5 Hz), 6.72 (d, 2H, J ) 7.5 Hz), 6.85 (d, 4H, J ) 9.0 Hz),
7.34 (d, 4H, J ) 9.0 Hz), 7.78 (d, 4H, J ) 10.5 Hz); 13C NMR
(100.5 MHz) δ 27.54, 32.19, 33.17, 33.90, 55.03, 69.32, 110.19,
126.16, 127.75, 129.82, 129.92, 131.10, 133.21, 134.49, 144.72
155.54; LRMS m/z 680 (M+), 525, 466, 368, 312, 256, 91. Anal.
Calcd for C37H44O8S2: C, 65.27; H, 6.51. Found: C, 65.43; H,
6.29.
Gen er a l Meth od for th e Rem ova l of MOM-P r otectin g
Gr ou p : 1,1′-(1,3-P r op a n ed iyl)bis[5-(3-h yd r oxyp r op yl)-2-
m eth oxyben zen e] (11a ). MOM-protected bis-anisole 10a
(6.24 g, 13.56 mmol) was dissolved in methanol (67.8 mL), the
solution was heated to reflux, and 12 M HCl (3.2 mL, 37.8
mmol) was added dropwise to the refluxing reaction mixture.
The solution was allowed to stir at reflux for 20 min and then
cooled to room temperature, and the solvent was removed
under vacuum. Saturated NaHCO3 solution (150 mL) was
added to the remaining oil to quench the reaction (pH ) 9).
The resulting solution was extracted with CH2Cl2 (4 × 100
mL), and the combined organic layers were washed with 100
mL brine, dried over Na2SO4, and concentrated under vacuum.
The crude solid was recrystallized from ethanol to yield 5.0 g
(13.4 mmol, 99%) of the title compound as white crystals: mp
1,1′-(1,4-Bu ta n ed iyl)bis[5-(4-(4-m eth ylben zen esu lfon -
yloxy)bu tyl)-2-m eth oxyben zen e] (12b). The reaction of bis-
anisole 11b (0.98 g, 2.37 mmol) with p-toluenesulfonyl chloride
(1.34 g, 7.13 mmol) in CH2Cl2 (4.7 mL) and pyridine (1.5 mL,
19.0 mmol) furnished, after purification by silica gel column
chromatography (75:25 hexane/ethyl acetate), 1.64 g (2.27
mmol, 96%) of the title compound as a clear oil: bp 156-157
°C; 1H NMR δ 1.63-1.98 (m, 12H), 2.45 (s, 6H), 2.54-2.65 (m,
8H), 3.83 (s, 6H), 4.02 (t, 4H, J ) 13.5 Hz), 6.73 (d, 2H, J )
7.5 Hz), 6.84 (d, 4H, J ) 9.0 Hz), 7.36 (d, 4H, J ) 9.0 Hz),
7.77 (d, 4H, J ) 10.5 Hz); 13C NMR (100.5 MHz) δ 26.94, 33.84,
34.32, 35.02, 56.48, 70.83, 111.32, 127.47, 129.23, 130.29,
131.65, 133.44, 135.83, 136.86, 146.30, 157.28; LRMS m/z 722
(M+), 567, 412, 256, 91. Anal. Calcd for C40H50O8S2: C, 66.46;
H, 6.97. Found: C, 66.54; H, 6.71.
1
42-44 °C; H NMR δ 1.34 (s, 2H), 1.81-1.93 (m, 6H), 2.56-
2.72 (m, 8H), 3.60-3.70 (m, 4H), 3.80 (s, 6H), 6.77 (d, 2H, J )
10.5 Hz), 6.94-7.03 (m, 4H); 13C NMR (100.5 MHz) δ 32.19,
33.17, 33.90, 55.03, 69.32, 111.84, 128.03, 128.89, 130.81,
133.78, 154.63; LRMS m/z 372 (M+), 359, 256, 91. Anal. Calcd
for C23H32O4: C, 74.16; H, 8.66. Found: C, 73.94; H, 8.87.
1,1′-(1,4-Bu ta n ed iyl)bis[5-(4-h yd r oxybu tyl)-2-m eth oxy-
ben zen e] (11b). The reaction of MOM-protected bis-anisole
10b (3.89 g, 7.74 mmol) in methanol (38.7 mL) and 12 M HCl
(1.8 mL, 21.6 mmol) furnished 2.92 g (7.05 mmol, 91%) of the
title compound as white crystals after recrystallization from
ethanol: mp 52-54 °C; 1H NMR δ 1.33 (s, 2H), 1.68-1.93 (m,
12H), 2.47-2.68 (m, 8H), 3.54-3.71 (m, 4H), 3.82 (s, 6H), 6.73
(d, 2H, J ) 10.5 Hz), 6.86-6.95 (m, 4H); 13C NMR (100.5 MHz)
δ 31.65, 32.85, 33.16, 34.05, 55.38, 69.64, 112.28, 128.53,
128.53, 130.52, 133.81, 153.94; LRMS m/z 414 (M+), 340, 256,
91. Anal. Calcd for C26H38O4: C, 75.32; H, 9.24. Found: C,
75.08; H, 9.43.
1,1′-(1,1′-(2,2′-Oxybiseth a n e)d iyl)bis[5-(3-(4-m eth ylben -
zen esu lfon yloxy)p r op yl)-2-m eth oxyben zen e] (12c). The
reaction of bis-anisole 11c (1.62 g, 4.02 mmol) with p-
toluenesulfonyl chloride (2.29 g, 12.1 mmol) in CH2Cl2 (8.1 mL)
and pyridine (2.6 mL, 32.3 mmol) furnished, after purification
by silica gel column chromatography (75:25 hexane/ethyl
acetate), 2.40 g (3.38 mmol, 84%) of the title compound as a
1
clear oil: bp 192-194 °C; H NMR δ 1.71-1.79 (m, 4H), 2.46
(s, 6H), 2.69 (t, 8H, J ) 9.0 Hz), 3.45-3.58 (m, 4H), 3.64-3.73
(m, 4H), 3.80 (s, 6H), 6.83 (d, 2H, J ) 7.5 Hz), 6.91-7.04 (m,
4H), 7.31 (d, 4H, J ) 9.0 Hz), 7.69 (d, 4H, J ) 10.5 Hz); 13C
NMR (100.5 MHz) δ 26.82, 31.27, 34.35, 56.03, 66.38, 69.72,
111.11, 121.83, 126.83, 129.29, 130.48, 132.83, 133.37, 135.02,
143.98, 158.87; LRMS m/z 710 (M+), 555, 496, 401, 363, 340,
286, 247, 91. Anal. Calcd for C38H46O9S2: C, 64.20; H, 6.52.
Found: C, 64.05; H, 6.74.
1,1′-(1,1′-(2,2′-Oxybiseth a n e)d iyl)bis[5-(3-h yd r oxyp r o-
p yl)-2-m et h oxyb en zen e] (11c). The reaction of MOM-
protected bis-anisole 10c (4.39 g, 8.95 mmol) in methanol (44.8
mL) and 18 M H2SO4 (0.7 mL, 13.8 mmol; H2SO4 was used in
place of HCl to avoid the nucleophilic chloride counterion)
furnished the crude product as an oil. Purification of the crude
oil by silica gel column chromatography (50:50 hexane/ethyl
acetate) yielded 3.10 g (7.70 mmol, 86%) of the title compound
as white crystals: mp 131-133 °C; 1H NMR δ 1.40 (s, 2H),
1.76-1.84 (m, 4H), 2.73 (t, 8H, J ) 9.0 Hz), 3.48-3.56 (m, 4H),
3.67-3.76 (m, 4H), 3.81 (s, 6H), 6.69 (d, 2H, J ) 7.5 Hz), 6.88-
1,1′-(1,6-Hexa n ed iyl)bis[5-(6-(4-m eth ylben zen esu lfon -
yloxy)h exyl)-2-m eth oxyben zen e] (12d ). The reaction of bis-
anisole 11d (0.37 g, 0.74 mmol) with p-toluenesulfonyl chloride
(0.42 g, 2.23 mmol) in CH2Cl2 (1.5 mL) and pyridine (0.48 mL,
5.93 mmol) furnished, after purification by silica gel column
chromatography (75:25 hexane/ethyl acetate), 0.55 g (0.69

5194 J . Org. Chem., Vol. 65, No. 17, 2000
Burns et al.
mmol, 93%) of the title compound as a clear oil: bp 166-168
exo-7,18,25,36-Tetr am eth oxy[4.4.4.4]m etacycloph an e (4).
The reaction of a Grignard solution, made from magnesium
turnings (0.78 g, 32.0 mmol) and 1,1′-(1,4-butanediyl)bis[5-
bromo-2-methoxybenzene] 9b (1.37 g, 3.20 mmol) in THF (6.4
mL), and a heated (60 °C) solution consisting of 1,1′-(1,4-
butanediyl)bis[5-(4-(4- methylbenzenesulfonyloxy)butyl)-2-
methoxybenzene] 12b (2.31 g, 3.20 mmol) dissolved in THF
(21.4 mL), HMPA (0.41 mL), and a total of 5.7 mL of 0.1 M
(LiBr/CuBr‚SMe2/LiSPh/THF) copper catalyst solution fur-
nished, after purification by radial chromatography (silica gel,
50:50 hexanes/CH2Cl2), 0.89 g (1.38 mmol, 43%) of the title
compound as a white solid: mp 134-136 °C; 1H NMR δ 1.65-
1.91 (m, 16H), 2.51-2.59 (m, 8H), 2.63-2.70 (m, 8H), 3.79 (s,
12 H), 6.71-6.77 (m, 4H), 6.88-6.97 (m, 8H); 13C NMR (100.5
MHz) δ 31.16, 32.03, 33.20, 34.87, 55.21, 110.37, 126.64,
128.92, 131.25, 134.83, 155.48; LRMS m/z 648 (M+), 394, 256,
91. Anal. Calcd for C44H56O4: C, 81.44; H, 8.70. Found: C,
81.38; H, 8.80.
1
°C; H NMR δ 1.20-1.41 (m, 12H), 1.47-1.64 (m, 12H), 2.41
(s, 6H), 2.44-2.62 (m, 8H), 3.77 (s, 6H), 3.99 (t, 4H, J ) 10.5),
6.76 (d, 2H, J ) 9.0 Hz), 6.90 (d, 4H, J ) 10.5 Hz), 7.33 (d,
4H, J ) 9.0 Hz), 7.79 (d, 4H, J ) 9.0 Hz); 13C NMR (100.5
MHz) δ 25.86, 26.16, 29.14, 29.53, 29.73, 30.01, 30.25, 31.76,
55.11, 71.28, 110.19, 126.16, 127.75, 129.82, 129.92, 131.10,
133.21, 134.49, 144.72, 155.54; LRMS m/z 807 (M+), 652, 551,
498, 447, 359, 297, 91. Anal. Calcd for C46H62O8S2: C, 68.45;
H, 7.74. Found: C, 68.52; H, 7.70.
Gen er a l P r oced u r e for th e P r ep a r a tion of exo-Tetr a -
m eth oxy[n .m .n .m ]m eta cyclop h a n e: exo-6,16,22,32-Tetr a -
m eth oxy[3.3.3.3]m eta cyclop h a n e (2a ). (a) The reaction was
performed under a nitrogen atmosphere in a Vacuum Atmo-
sphere glovebox. THF (4.6 mL) was added to magnesium
turnings (1.19 g, 49.0 mmol), and the reaction mixture was
heated to 60 °C. A solution of 1,1′-(1,3-propanediyl)bis[5-bromo-
2-methoxybenzene] (9a ) (2.03 g, 4.90 mmol) dissolved in THF
(5.2 mL) was transferred into the reaction mixture via a
syringe at a rate of 0.17 mL/min, and the resulting Grignard
solution was stirred at 60 °C for 20 h and then cooled to room
temperature. A solution consisting of 1,1′-(1,3-propanediyl)-
bis[5-(3-(4-methylbenzenesulfonyloxy)propyl)-2-methoxyben-
zene] (12a ) (3.33 g, 4.90 mmol) dissolved in THF (32.7 mL),
HMPA (0.62 mL, 6% v/v based on the volume of the Grignard
solution), and 5.9 mL (12 mol %) of 0.1 M (LiBr/CuBr‚SMe2/
LiSPh/THF) copper catalyst solution was heated to 60 °C. The
Grignard solution, decanted from excess magnesium turnings,
was added into the reaction mixture via a syringe at a rate of
0.33 mL/min. After 2 h, an additional 3.0 mL (6 mol %) of 0.1
M (LiBr/CuBr‚SMe2/LiSPh/THF) copper catalyst solution was
added, and the reaction mixture was allowed to stir at 60 °C
for an additional 72 h. The mixture was then cooled to room
temperature, removed from the glovebox, quenched with 1.5
M HCl (50 mL), and extracted with CH2Cl2 (4 × 30 mL). The
combined organic layers were washed with a second portion
of 1.5 HCl (50 mL), followed by brine (50 mL), dried over
Na2SO4, and concentrated under vacuum to yield an yellowish
oil. The crude product was purified by radial chromatography
(silica gel, 50:50 hexanes/CH2Cl2) to yield 2.03 g (3.43 mmol,
70%) of the title compound as a white solid.
(b) The following procedure is not a general preparation of
tetramethoxy[n.n.n.n]metacyclophanes, but is limited to n )
3 due to constraints on the macrocyclic yield when n > 3. THF
(3.7 mL) was added to magnesium turnings (0.96 g, 39.3 mmol)
and the reaction mixture heated to reflux. A solution of 1,1′-
(1,3-propanediyl)bis[5-bromo-2-methoxybenzene] (9a ) (1.62 g,
3.93 mmol) dissolved in of THF (4.20 mL) was transferred into
the reaction mixture via a syringe at a rate of 0.14 mL/min,
and the resulting Grignard solution was stirred at reflux for
20 h and then cooled to room temperature. A second solution
consisting of 1,3-propanediol, bis(4-methylbenzenesulfonate)
(13a ) (1.51 g, 3.93 mmol) dissolved in THF (26.2 mL), HMPA
(0.50 mL, 6% v/v based on the volume of the Grignard
solution), and 4.7 mL (12 mol %) of 0.1 M (LiBr/CuBr‚SMe2/
LiSPh/THF) copper catalyst solution was heated to reflux. The
Grignard solution, decanted from excess magnesium turnings,
was added to the refluxing solution with a cannulating needle.
After 2 h, an additional 2.4 mL (6 mol %) of 0.1 M (LiBr/CuBr‚
SMe2/LiSPh/THF) copper catalyst solution was added, and the
reaction mixture was allowed to stir at reflux for an additional
72 h. The reaction was then cooled to room temperature,
quenched with 1.5 M HCl (50 mL), and extracted with CH2Cl2
(4 × 30 mL). The combined organic layers were washed with
a second portion of 1.5 HCl (50 mL), followed by brine (50 mL),
dried over Na2SO4, and concentrated under vacuum to yield a
yellowish oil. The crude product was purified by radial
chromatography (silica gel, 50:50 hexanes/CH2Cl2) to yield 0.93
g (1.57 mmol, 40%) of the title compound as a white solid: mp
120-122 °C; 1H NMR δ 1.77-1.88 (m, 8H), 2.53-2.58 (m, 8H),
2.61-2.67 (m, 8H), 3.78 (s, 12 H), 6.72-6.75 (m, 4H), 6.92-
6.95 (m, 8H); 13C NMR (100.5 MHz) δ 30.07, 30.34, 34.41,
35.30, 55.44, 110.14, 126.45, 129.40, 130.99, 134.36, 155.57;
LRMS m/z 592 (M+), 336, 256, 91. Anal. Calcd for C40H48O4:
C, 81.04; H, 8.16. Found: C, 80.82; H, 8.23.
exo-8,18,26,36-Tet r a m et h oxy[5.3.5.3]-4,22-d ioxa m et a -
cyclop h a n e (5). The reaction of a Grignard solution, made
from magnesium turnings (0.76 g, 31.3 mmol) and 1,1′-(1,1′-
(2,2′-oxybisethane)diyl)bis[5-bromo-2-methoxybenzene] 9c (1.39
g, 3.13 mmol) in THF (6.3 mL), and a heated (60 °C) solution
consisting of 1,1′-(1,1′-(2,2′-oxybisethane)diyl)bis[5-(3-(4-meth-
ylbenzenesulfonyloxy)propyl)-2-methoxybenzene] 12c (2.23 g,
3.13 mmol) dissolved in THF (20.8 mL), HMPA (0.4 mL), and
a total of 5.7 mL of 0.1 M (LiBr/CuBr‚SMe2/LiSPh/THF) copper
catalyst solution furnished, after purification by radial chro-
matography (silica gel, 50:50 hexanes/CH2Cl2, 0.63 g (0.97
mmol, 31%) of the title compound as a white solid: mp 167-
169 °C; 1H NMR δ 1.62-1.77 (m, 4H), 2.42-2.71 (m, 16H),
3.48-3.56 (m, 8H), 3.77 (s, 12H), 6.75-6.91 (m, 4H), 7.21-
7.35 (m, 8H); 13C NMR (100.5 MHz) δ 32.81, 35.94, 55.48,
67.47, 111.37, 122.93, 128.25, 131.38, 133.84, 159.35; LRMS
m/z 652 (M+), 368, 286, 91. Anal. Calcd for C42H52O6: C, 77.27;
H, 8.03. Found: C, 77.29; H, 7.95.
exo-9,22,31,44-Tetr am eth oxy[6.6.6.6]m etacycloph an e (6).
The reaction of a Grignard solution, made from magnesium
turnings (0.96 g, 39.3 mmol) and 1,1′-(1,6-hexanediyl)bis[5-
bromo-2-methoxybenzene] 9d (1.62 g, 3.93 mmol) in THF (7.9
mL), and a heated (60 °C) solution consisting of 1,1′-(1,6-
hexanediyl)bis[5-(6-(4-methylbenzenesulfonyloxy)hexyl)-2-meth-
oxybenzene] (12d ) (1.51 g, 3.93 mmol) dissolved in THF (26.2
mL), HMPA (0.5 mL), and a total of 7.1 mL of 0.1 M (LiBr/
CuBr‚SMe2/LiSPh/THF) copper catalyst solution furnished,
after purification by radial chromatography (silica gel, 50:50
hexanes/CH2Cl2), 0.95 g (1.25 mmol, 40%) of the title compound
1
as a white solid: mp 146-147 °C; H NMR δ 1.34-1.42 (m,
16H), 1.49-1.67 (m, 16H), 2.46-2.62 (m, 16H), 3.75 (s, 12H),
6.81-6.90 (m, 4H), 7.10-7.19 (m, 8H); 13C NMR (100.5 MHz)
δ 29.16, 29.55, 29.80, 29.97, 31.69, 35.08, 55.29, 110.05, 126.16,
130.98, 131.03, 134.46, 155.42; LRMS m/z 760 (M+), 464, 297,
91. Anal. Calcd for C52H72O4: C, 82.06; H, 9.53. Found: C,
82.11; H, 9.49.
exo-6,16,22,32-Tet r a h yd r oxy[3.3.3.3]m et a cyclop h a n e
(2b). To a solution of tetramethoxy[3.3.3.3]metacyclophane 2a
(0.070 g, 0.118 mmol) in ClCH2CH2Cl (3.0 mL), cooled to 0 °C
in an ice-bath, was added a solution of BBr3‚SMe2 (0.592 g,
2.36 mmol) in ClCH2CH2Cl (5 mL) at a rate of 0.17 mL/min
via a syringe. After the addition was complete, the reaction
mixture was allowed to gradually warm to room temperature
and stirred for 16 h. The reaction mixture was quenched with
H2O (10 mL) and extracted with Et2O (2 × 50 mL), and the
combined ether layers were extracted with 10% NaHCO3 (100
mL) and then were further extracted with 1 M NaOH (3 × 25
mL). The combined aqueous layers were acidified with 3 M
HCl and extracted with Et2O (3 × 50 mL). The combined
organic layers were then dried over Na2SO4 and concentrated
under vacuum. The crude solid was purified by radial chro-
matography (silica gel, 60:40 hexanes/ethyl acetate) to yield
0.0585 g (0.108 mmol, 92%) of the title compound as a white
solid: mp 170-172 °C; 1H NMR (acetone-d6) δ 1.73-1.92 (m,
8H), 2.53 (t, 8H, J ) 8.0 Hz), 2.67 (t, 8H, J ) 7.9 Hz), 6.69-
6.71 (m, 4H), 6.81-6.85 (m, 8H), 6.90-6.92 (s, 4H); 13C NMR

exo-[n.m.n.m]Metacyclophanes, n,m g 3
J . Org. Chem., Vol. 65, No. 17, 2000 5195
(DMSO-d6, 75.43 MHz) δ 29.56, 30.20, 34.27, 34.47, 114.60,
126.27, 128.08, 129.09, 132.19, 152.82; LRMS m/z 536 (M+),
280, 256, 91. Anal. Calcd for C36H40O4: C, 80.56; H, 7.51.
Found: C, 80.19; H, 7.72.
1,1′-(1,3-P r op a n ed iyl)bis[5-(3-br om obu tyl)-2-m eth oxy-
ben zen e] (17a ). Bis-anisole 9a (1.12 g, 2.70 mmol) dissolved
in THF (3 mL) was added at a rate of 0.33 mL/min to a solution
of magnesium turnings (0.27 g, 11.13 mmol) in THF (8 mL).
The resulting bis-Grignard was stirred at reflux for 16 h and
then cooled to room temperature. The Grignard solution was
cannulated into another solution containing 1,4-dibromopro-
pane (5.84 g, 27.0 mmol) and 0.83 mL (3 mol %) of 0.1 M
Li2CuBr4/THF copper catalyst solution maintained at 0 °C. The
mixture was allowed to gradually warm to room temperature,
and after 3 h another 0.83 mL of 0.1 M Li2CuBr4/THF was
added. After 6 h a third portion of 0.83 mL of 0.1 M Li2CuBr4/
THF was added. After 48 h the reaction was quenched with
H2O (100 mL) and extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were washed with 10% HCl (100 mL),
H2O (100 mL), brine (100 mL), dried over Na2SO4, and
concentrated under vacuum. The crude product was purified
by radial chromatography (silica gel, 98:2 hexanes/ethyl
acetate) to yield 0.636 g (1.22 mmol, 45%) of the title compound
as a clear oil: bp > 300 °C; 1H NMR δ 1.69-1.80 (m, 4H),
1.81-1.95 (m, 6H), 2.56 (t, 4H, J ) 7.3 Hz), 2.65 (t, 4H, J )
7.7 Hz), 3.40 (t, 4H, J ) 6.6 Hz), 3.79 (s, 6H), 6.73-6.77 (m,
2H), 6.94-6.95 (m, 4H); 13C NMR (75.43 MHz) δ 29.86, 30.15,
32.33, 33.69, 34.19, 55.45, 110.29, 126.35, 129.81, 131.04,
133.49, 155.85. Anal. Calcd for C25H34Br2O2: C, 57.05; H, 6.51.
Found: C, 57.08; H, 6.53.
exo-6,16,22,32-Tetr aacetoxy[3.3.3.3]m etacycloph an e (18).
A solution of exo-tetrahydroxy[3.3.3.3]metacyclophane 2b
(0.311 g, 0.579 mmol) and triethylamine (0.16 mL, 1.157 mmol)
in THF (2.90 mL, 0.20 M) was heated to reflux, and acetyl
chloride (0.11 mL, 1.45 mmol) was added dropwise to the
refluxing solution. The reaction was allowed to stir for 24 h
before being cooled to room temperature and quenched with
10 mL of NaHCO3. The reaction mixture was then extracted
with CH2Cl2 (4 × 10 mL), dried over Na2SO4, and concentrated
under vacuum to yield a clear oil. The crude product was
purified by radial chromatography (silica gel, 45:55 hexanes/
CH2Cl2) to yield 0.345 g (0.49 mmol, 85%) of the title compound
1
as a white solid: mp 137-139 °C; H NMR δ 1.64-1.91 (m,
8H), 2.09 (s, 12H), 2.56 (t, 8H, J ) 8.0 Hz), 2.70 (t, 8H, J )
7.9 Hz), 6.64-6.68 (m, 4H), 6.82-6.87 (m, 4H), 6.92-7.05 (m,
4H); 13C NMR (100.5 MHz) δ 29.77, 30.54, 35.04, 35.18, 58.57,
115.12, 125.68, 127.84, 129.35, 133.31, 153.87, 172.93; LRMS
m/z 704 (M+), 644, 585, 328, 256, 91. Anal. Calcd for
C
44H48O8: C, 74.98; H, 6.86. Found: C, 74.71; H, 6.99.
Mon o-(m eth ylen e-lin k ed )-exo-6,16,22,32-tetr a h yd r oxy-
[3.3.3.3]m eta cyclop h a n e (19). A reaction mixture consisting
of exo-tetrahydroxy[3.3.3.3]metacyclophane 2b (0.167 g, 0.310
mmol), K2CO3 (0.0902 g, 0.653 mmol), and bromochloro-
methane (20 µL, 0.310 mmol) in DMSO (14.4 mL) was heated
to 60 °C for 20 h (the course of the reaction was followed by
TLC to confirm the attachment of the chloromethane moiety).
At this point, the reaction mixture was then heated to 120 °C
and stirred for 48 h to complete the ring formation. The
reaction was then allowed to cool to room temperature,
quenched with a saturated solution of NaHCO3 (10 mL), and
extracted with CH2Cl2 (4 × 10 mL), and the combined organic
layers dried over Na2SO4 and concentrated under vacuum to
yield a clear oil. The crude product was purified by radial
chromatography (silica gel, 45:55 hexanes/CH2Cl2) to yield
0.107 g (0.0196 mmol, 63%) of compound 19 as a white solid:
1,1′-(1,3-P r opan ediyl)bis[5-(5-br om open tyl)-2-m eth oxy-
ben zen e] (17b). The procedure is the same as above. Thus, a
Grignard solution made from bis-anisole 9a (1.01 g, 2.43 mmol)
and magnesium turnings (0.236 g, 9.73 mmol) in THF (10 mL)
was added to a solution containing 1,5-dibromopentane (5.60
g, 24.3 mmol) and a total of 2.25 mL 0.1 M Li2CuBr4/THF
copper catalyst solution to yield, after purification by radial
chromatography (silica gel, 98:2 hexanes/ethyl acetate), 0.80
g (1.46 mmol, 60%) of the title compound as a clear oil: bp >
300 °C; 1H NMR δ 1.40-1.52 (m, 4H), 1.55-1.68 (m, 4H),
1.82-1.97 (m, 6H), 2.53 (t, 4H, J ) 7.4 Hz), 2.65 (t, 4H, J )
7.8 Hz), 3.39 (t, 4H, J ) 6.9 Hz), 3.79 (s, 6H), 6.75-6.77 (m,
2H), 6.90-6.95 (m, 4H); 13C NMR (75.43 MHz) δ 27.99, 29.97,
30.32, 31.06, 32.89, 33.94, 35.06, 55.57, 110.33, 126.43, 129.93,
131.04, 134.12, 155.84. Anal. Calcd for C27H38Br2O2: C, 58.49;
H, 6.91. Found: C, 58.38; H, 6.93.
1
mp 155-157 °C; H NMR (acetone-d6) δ 1.74-1.94 (m, 8H),
2.50 (t, 8H, J ) 10.5 Hz), 2.63 (t, 4H, J ) 10.5 Hz), 2.84 (t,
4H, J ) 7.5 Hz), 5.98 (s, 2H), 6.60 (d, 2H, J ) 7.5 Hz), 6.72 (d,
2H, J ) 7.5 Hz), 6.82-6.96 (m, 10 H); 13C NMR (100.5 MHz)
δ 28.08, 31.41, 36.10, 36.96, 96.54, 115.63, 116.84, 123.49,
124.67, 126.37, 127.84, 128.52, 131.54, 132.98, 149.76, 151.31;
LRMS m/z 548 (M+), 534, 292, 256, 91. Anal. Calcd for
exo-6,17,23,33-Tetr am eth oxy[3.4.3.4]m etacycloph an e (7).
Bis-anisole 9a (0.897 g, 2.16 mmol) dissolved in THF (4 mL)
was added at a rate of 0.33 mL/min to a solution of magnesium
turnings (0.210 g, 8.66 mmol) in THF (8 mL). The resulting
bis-Grignard was stirred at reflux for 16 h and then cooled to
room temperature. A second solution consisting of bis-anisole
17a (0.570 g, 1.08 mmol) dissolved in THF (10 mL) and the
bis-Grignard solution were both added simultaneously to a
third refluxing solution containing CuBr‚SMe2 (0.25 g, 1.12
mmol), HMPA (2.0 mL), and THF (10.0 mL). After 40 h of
stirring at reflux, the reaction was cooled to room temperature
and quenched with 10% NH4Cl (100 mL) and extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed
with 3 M HCl (3 × 100 mL), water (100 mL), and brine (100
mL), dried over Na2SO4, and concentrated under vacuum. The
crude product was purified by radial chromatography (silica
gel, 50:50 hexanes/CH2Cl2) to yield 0.073 g (0.24 mmol, 11%)
of the title compound as a white solid: mp 184-185 °C; 1H
NMR δ 1.60-1.67 (m, 8H), 1.85-1.95 (m, 4H), 2.53-2.61 (m,
8H), 2.61 (t, 8H, J ) 7.8 Hz), 3.78 (s, 12H), 6.72-6.75 (m, 4H),
6.93-6.98 (m, 8H); 13C NMR (75.43 MHz) δ 29.03, 29.50, 31.39,
35.13, 55.43, 110.15, 126.26, 129.86, 130.68, 134.31, 155.67;;
LRMS m/z 621 (M+), 592, 508, 429, 349, 323, 310. Anal. Calcd
for C42H52O4: C, 81.25; H, 8.44, Found: C, 80.32; H, 8.71.
C
37H40O4: C, 80.99; H, 7.35. Found: C, 80.61; H, 7.54.
Bis-(m et h ylen e-lin k ed )-exo-6,16,22,32-t et r a h yd r oxy-
[3.3.3.3]m eta cyclop h a n e (20). A reaction mixture consisting
of exo-metacyclophane 19 (0.100 g, 0.18 mmol), K2CO3 (0.0530
g, 0.382 mmol), and bromochloromethane (12 µL, 0.18 mmol)
in DMSO (8.47 mL) was heated to 60 °C for 20 h (the course
of the reaction was followed by TLC to confirm the attachment
of the chloromethane moiety). The reaction was then heated
to 160 °C and allowed to stir for 168 h to complete the ring
formation. The reaction was then allowed to cool to room
temperature, quenched with a saturated solution of NaHCO3
(10 mL), and extracted with CH2Cl2 (4 × 10 mL), and the
combined organic layers were dried over Na2SO4 and concen-
trated under vacuum to yield a clear oil. The crude product
was purified by radial chromatography (silica gel, 55:45
hexanes/CH2Cl2) to yield 0.055 g (0.098 mmol, 54%) of com-
pound 20 as a white solid: mp 137-139 °C; 1H NMR δ 1.70-
1.98 (m, 8H), 2.54 (t, 8H, J ) 8.0 Hz), 2.72 (t, 8H, J ) 7.9 Hz),
5.91 (s, 4H), 6.69-6.71 (m, 4H), 6.81-6.85 (m, 8H); 13C NMR
(100.5 MHz) δ 28.64, 31.08, 35.25, 36.58, 96.74, 116.96, 124.30,
126.14, 128.64, 132.89, 151.31; LRMS m/z 560 (M+), 549, 535,
304, 256, 91. Anal. Calcd for C38H40O4: C, 81.40; H, 7.19.
Found: C, 81.61; H, 7.08.
exo-6,18,24,36-Tetr am eth oxy[3.5.3.5]m etacycloph an e (8).
The procedure is the same as that above. Thus, a Grignard
solution made from bis-anisole 9a (0.53 g, 1.28 mmol) and
magnesium turnings (0.125 g, 5.14 mmol) in THF (6.5 mL)
was added to a solution consisting of bis-anisole 17b (0.32 g,
0.58 mmol), HMPA (1.5 mL), CuBr‚SMe2 (0.13 g, 0.64 mmol),
and THF (17.5 mL) to yield, after purification by radial
The following experimentals are examples of our previous
methods used to prepare exo-metacyclophane 7 and 8 before
the development of the soluble copper catalyst and the routine
use of tosylate-MOM electrophiles and are included for pur-
poses of comparison.

5196 J . Org. Chem., Vol. 65, No. 17, 2000
Burns et al.
chromatography (silica gel, 50:50 hexanes/CH2Cl2), 0.088 g
(0.29 mmol, 23%) of the title compound as a white solid: mp
131-134 °C; 1H NMR δ 1.30-1.45 (m, 4H), 1.53-1.66 (m, 8H),
1.79-1.93 (m, 4H), 2.50 (t, 8H, J ) 7.8 Hz), 2.60-2.68 (m, 8H),
3.78 (s, 12H), 6.72 (d, 4H, J ) 6.0 Hz), 6.93 (m, 8H); 13C NMR
(75.43 MHz) δ 29.27, 29.87, 29.95, 32.02, 35.24, 55.45, 110.16,
126.32, 129.58, 130.88, 134.68, 155.60. Anal. Calcd for
NSF in the purchase of a departmental 400 MHz NMR
(CHE-9700421).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H NMR,
13C NMR, and LRMS spectra of 2a , 4-8, and 18-20 and, an
X-ray crystallographic report for 2a and 6 and, experimentals
and characterizations for compounds 13b-13d , 14a -14c, and
15a -15c. This material is available free of charge via the
Internet at http://pubs.acs.org.
C
44H56O4: C, 81.44; H, 8.70. Found: C, 81.33; H, 8.53.
Ack n ow led gm en t. D.H.B. and D.M.E. gratefully
acknowledge the support of this work by the National
Science Foundation (EPS-9550487) and the support of
J O0003044