Synthesis of cyclophanes with intra-annular functionality and cage structure

Article abstract of DOI:10.1021/jo950957y

Cyclophanes of the type 1 and 2, with large cavity sizes, have been synthesized from the corresponding dichloride 8 or 8a and o-xylene-α,α′-dithiol (9), p-xylene-α,α′-dithiol (10), or m-terphenyldithiol (11). Similarly, cyclophanes of the type 3 with intr

Full text of DOI:10.1021/jo950957y

5090
J . Org. Chem. 1996, 61, 5090-5102
Syn th esis of Cyclop h a n es w ith In tr a -An n u la r F u n ction a lity a n d
Ca ge Str u ctu r e
Arunachalam Kannan,† Perumal Rajakumar,*,†,‡ V. Kabaleeswaran,§ and S. S. Rajan§,|
Departments of Organic Chemistry and Crystallography and Biophysics, University of Madras,
Guindy Campus, Guindy, Madras 600 025, India
Received May 25, 1995 (Revised Manuscript Received April 2, 1996X)
Cyclophanes of the type 1 and 2, with large cavity sizes, have been synthesized from the
corresponding dichloride 8 or 8a and o-xylene-R,R′-dithiol (9), p-xylene-R,R′-dithiol (10), or
m-terphenyldithiol (11). Similarly, cyclophanes of the type 3 with intra-annular functionality have
been obtained by the coupling of the corresponding dithiol 15 or 19 and m-terphenyl dibromide 5,
5a , 5b, or 5c. With the aim of introducing multifunctionality, cyclophanes of the type 21 and 23
were prepared from 3,5-bis(mercaptomethyl)anisole or 3,5-bis(mercaptomethyl)phenol and the
corresponding substituted m-terphenyl dibromide 5b or 5c. Cyclophanes 24, 24a , 24b, and 32,
with a new type of cage structure, have been obtained by the coupling of the corresponding tetrathiol
29 with 2 equiv of the dibromides 5c, 5a , and 5b or 1 equiv of the tetrabromide 31, respectively.
1
Further, the sodium salts of the cyclophanes 3c, 21, and 24b were completely characterized by H
NMR spectroscopy. XRD analysis of the cyclophane 21 revealed the presence of an ethanol molecule
inside the cavity, indicating the facile formation of a host-guest complex.
In tr od u ction
Cyclophanes in general can be used as host molecules
for complexation of either metal ions or small guest
molecules. The cyclophanes reported here have different
molecular cavity size and therefore can be used for
specific complexation. The aromatic units present in
these cyclophanes ensure the necessary rigidity8 and
prevent the possible collapse of conformation which would
reduce the cavity size.
Molecules with large cavities, and supramolecular
chemistry in general, are of great current interest.1
Though the synthesis of unstable syn-[2,2]metacyclo-
phane was reported in 1985,2 the modified cyclophanes
called cuppedophanes and cappedophanes were only
reported recently.3 Thiacyclophanes have proved to be
remarkably useful precursors to a number of novel
compounds.4 For example, Mitchell has recently reported
the synthesis of novel aromatic systems via thiacyclo-
phane.5 Examples of the synthesis of dithiacyclophanes
containing large molecular cavities have been reported
by our laboratory.6 The synthesis of functionalized
cyclophanes has been an active research area recently
with particular focus on hydrophilic cavities.7
We wish to report the synthesis of cyclophanes with
large cavities that contain varied functionality. This
permits a comparison of functional group chemistry
within the outside a specifically designed microenviron-
ment. Further, we report the synthesis of a new class of
cyclophanes which contain a cage structure. We also
discuss the formation of the sodium salt as well as the
host-guest complex of some of the cyclophanes.
Resu lts a n d Discu ssion
Cyclop h a n es w ith Ma cr ocyclic Ca vities. Cyclo-
phanes 1-3 are based on a m-terphenyl framework that
can be obtained by the known tandem aryne sequence.9
The angular nature of the m-terphenyl present in com-
pounds 1-3 prompted us to use substituted m-terphenyl
as the basic building block. Addition of 3 equiv of
p-tolylmagnesium bromide to 2,6-dichloroiodobenzene
followed by quenching with dilute HCl, Br2, or CO2
resulted in the formation of 4,4′′-dimethyl-1,1′:3′,1′′-
terphenyl (4), 2′-bromo-4,4′′-dimethyl-1,1′:3′,1′′-terphenyl
(4a ), or 4,4′′-dimethyl-1,1′:3′,1′′-terphenyl-2′-carboxylic
acid (4b) in excellent yield. The bromide 4a can also be
prepared by treating the reaction mixture of aryl Grig-
nard and dichloroiodobenzene with CBr4. Treatment of
the carboxylic acid 4b with CH2N2 in THF gave methyl
ester 4c, which can also be prepared by refluxing the acid
chloride of 4b with MeOH. Twofold radical bromination
of 4, 4a , 4b, and 4c with NBS in CCl4 gave 4,4′′-bis-
(bromomethyl)-1,1′:3′,1′′-terphenyl (5), 2′-bromo-4,4′′-bis-
(bromomethyl)-1,1′:3′,1′′-terphenyl (5a ), 4,4′′-bis(bromo-
methyl)-1,1′:3′,1′′-terphenyl-2′-carboxylic acid (5b), and
methyl 4,4′′-bis(bromomethyl)-1,1′:3′,1′′-terphenyl-2′-car-
boxylate (5c) in 80, 75, 65, and 60% yields, respectively.
Bisalkylation of the dibromides 5 and 5a with methyl
p-hydroxybenzoate in the presence of K2CO3 in DMF
afforded the diesters 6 and 6a in 85 & 75% yields
respectively. LAH reduction of the diesters 6 and 6a
followed by treatment with SOCl2 in the presence of
† Department of Organic Chemistry.
‡ Present Address: Department of Chemistry, Indian Institute of
Technology, Madras 600 036, India.
§ Department of Crystallography and Biophysics.
| To whom inquiries regarding X-ray structures should be directed.
X Abstract published in Advance ACS Abstracts, May 15, 1996.
(1) For reviews and some examples, see: (a) Cram, D. J . Angew.
Chem., Int. Ed. Engl. 1988, 27, 1009. (b) Diederich, F. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 362. (c) Ferguson, S. B.; Seward, E. M.;
Sanford, E. M.; Hester, M.; Uyeki, M>; Diederich, F. Pure Appl. Chem.
1989, 61, 1523. (d) J imenez, L.; Diederich, F. Tetrahedron Lett. 1989,
30, 2759. (e) Breitenbach, J .; Vo¨gtle, F. Synthesis 1992, 41. (f) Seel,
C.; Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1992, 31, 528. (g) Lee, W.
Y.; Park, C. H.; Kim, H. J .; Kim, S. S. J . Org. Chem. 1994, 59, 878. (h)
Diederich, F.; Carcanague, D. R. Helv. Chim. Acta 1994, 77, 800. (i)
Hart, H.; Rajakumar, P. Tetrahedron 1995, 51, 1313. (j) Vinod, T. K.;
Rajakumar, P.; Hart, H. Tetrahedron 1995, 51, 2267.
(2) Mitchell, R. H.; Vinod, T. K. J . Am. Chem. Soc. 1985, 107, 3340.
(3) (a) Vinod, T. K.; Hart, H. J . Am. Chem. Soc. 1988, 110, 6574.
(b) Vinod, T. K.; Hart, H. J . Org. Chem. 1990, 55, 881.
(4) Mitchell, R. H. Heterocycles 1978, 11, 563.
(5) Mitchell, R. H.; Zhang, J . Tetrahedron Lett. 1995, 36, 1177.
(6) Rajakumar, P.; Kannan, A. Tetrahedron Lett. 1993, 34, 4407.
(7) Hart, H. Pure Appl. Chem. 1993, 65, 27.
(8) J arvi, E. T.; Whitlock, H. W. J . Am. Chem. Soc. 1982, 104, 7196.
(9) (a) Du, C. J . F.; Hart, H.; Ng, K. K. D. J . Org. Chem. 1986, 51,
3162. (b) Hart, H.; Ghosh, T. Tetrahedron Lett. 1988, 29, 881.
S0022-3263(95)00957-1 CCC: $12.00 © 1996 American Chemical Society

Synthesis of Intra-Annular Cyclophanes
J . Org. Chem., Vol. 61, No. 15, 1996 5091
treated with 1 equiv of n-BuLi at -78 °C followed by
quenching with dilute HCl afforded, quantitatively, the
cyclophanes 1a and 1c, respectively, indicating the
generation of the lithium salt and demonstrating that
the reaction permits the introduction of various func-
tionalities at the C2′ position of the m-terphenyl frame-
work.
With the intent of further increasing the cavity size,
the dichlorides 8 and 8a were coupled with 4,4′′-bis-
(mercaptomethyl)-1,1′:3′,1′′-terphenyl (11) obtained from
the dibromide 5 by application of the known standard
procedure using KOH.9 The coupling, after usual work-
up, afforded the cyclophanes 2a and 2b in 30 and 25%
yields (Scheme 2), respectively, as supported by the
spectral data and satisfactory elemental analysis.
Our attention was then focused on changing the
positions of the S and O atoms to result in the formation
of cyclophanes of the type 3. Bisalkylation of o-xylene
R,R′-dibromide with methyl p-hydroxybenzoate in K2CO3/
DMF afforded the diester 12 in 90% yield. The dithiol
15 was obtained in an overall yield of 51% from the
diester 12 by the conventional route.11 Similarly, the
dithiol 19 was obtained by the hydrolysis of the isothio-
uronium salt derived from the corresponding diester 16
(Scheme 3).
Coupling of the dithiol 15 with 1 equiv of the dibromide
5 in benzene under high dilution in the presence of KOH
in ethanol afforded the cyclophane 3a in 70% yield
1
(Scheme 4). The H NMR spectrum of 3a showed three
singlets of four protons each at δ 3.60, 3.65, and 5.25 for
the CH2S, SCH2, and OCH2 protons, respectively, in
addition to the aromatic protons. The o-xylylenyl protons
in 3a each appeared as a two-proton multiplet at δ 7.09-
7.19 and 7.17-7.21, respectively. Similarly, coupling of
the dithiol 19 with 1 equiv of the dibromide 5 gave the
pyridine in CH2Cl2 resulted in the dichlorides 8 and 8a
in 82 and 77% yields, respectively (Scheme 1).
1
cyclophane 3e (65%) as evidenced by the H NMR and
13C NMR spectra.
Coupling of the dichlorides 8 and 8a with o-xylene-
R,R′-dithiol (9) in benzene under high dilution in the
presence of KOH in ethanol afforded the cyclophanes 1a
and 1b in 70 & 60% yields, respectively (Scheme 2).
The 1H NMR spectrum of 1a showed three singlets
each of four protons at δ 3.60, 3.65, and 5.25 for CH2S,
SCH2, and OCH2, respectively, in addition to the aromatic
protons. The C2H of the m-terphenyl frame appeared as
a one-proton triplet at δ 7.67. The fact that the chemical
shift of the C2H of the m-terphenyl unit is not affected
suggests that this hydrogen is not in the π-cloud of the
o-xylylene unit. The 1H NMR spectrum of 1b showed the
absence of a C2H proton. Structures 1a and 1b were
further supported by their 13C NMR and mass spectra.
XRD10 studies on 1a also confirmed the structure. The
Ortep, unit cell packing, and CPK space-filling diagrams
of cyclophane 1a are shown in Figures 1, 2, and 3,
respectively.
Cyclop h a n es w ith F u n ction a lized Micr oen vir on -
m en t. The introduction of functional groups into the
microenvironment of the cyclophane cavity comprised the
next phase of this project.
The synthetic strategy was directed toward cyclo-
phanes with intra-annular functionality. The dithiol 15
(Scheme 3) in benzene when coupled with the dibromide
5a under high-dilution technique in the presence of KOH
in ethanol afforded the cyclophane 3b. Similarly, cyclo-
phane 3f was obtained from the dithiol 19 and the
dibromide 5a (Scheme 4). Coupling of the dithiol 15 with
the dibromide 5b in the presence of 3 equiv of KOH,
followed by acidification of the reaction mixture before
the usual workup, yielded the cyclophane 3c. Similarly,
cyclophane 3g was obtained from the dithiol 19 and the
dibromide 5b. In 3c and 3g the carboxylic acid group is
in the microenvironment of the cyclophane. Cyclophanes
3c and 3g were also obtained from the cyclophanes 3b
and 3f using n-BuLi and CO2. The lithium salt of
cyclophanes 3b and 3f upon bubbling with dry CO2 for 3
h followed by acidification gave the cyclophanes 3c and
3g in good yield. Acidification of the lithium salt from
3b and 3f with dilute HCl afforded the cyclophanes 3a
and 3e in excellent yield. Coupling of the dithiol 15 or
19 with the dibromide 5c in benzene using KOH in
ethanol afforded the cyclophanes 3d and 3h with a
COOMe group in the microenvironment. Cyclophanes
3d and 3h were also obtained from 3c and 4c, respec-
Similar coupling of the dichlorides 8 and 8a with
p-xylene-R,R′-dithiol (10) under identical conditions gave
the cyclophanes 1c and 1d in 60 and 55% yields,
respectively. The 1H NMR spectrum of 1c displayed
three singlets of four protons each at δ 3.49, 3.55, and
1
5.25 for the CH2S, SCH2, and OCH2 protons. In the H
NMR spectrum, the p-xylylene protons of 1d appeared
as a singlet at δ 7.16 indicating free rotation and a lack
of shielding of these protons by the bromine atom at the
C2′ position. The bromo compounds 1b and 1d when
(10) Kabaleeswaran, V.; Rajan, S. S.; Kannan, A.; Rajakumar, P.
Acta Crystallogr. C, submitted.
(11) Vinod, T. K.; Hart, H. J . Org. Chem. 1991, 56, 5630.

5092 J . Org. Chem., Vol. 61, No. 15, 1996
Kannan et al.
Sch em e 1
F igu r e 3. CPK space-filling model of cyclophane 1a .
F igu r e 1. Ortep diagram of the cyclophane 1a .
SOCl2 in CH2Cl2 with few drops of pyridine and then to
heat the reaction mixture in refluxing methanol. How-
ever, quantitative yields were obtained upon reaction
with CH2N2.
It is worth mentioning that the p-xylylenyl group in
the cyclophanes 3e, 3f, 3g, and 3h showed free rotation,
as revealed by the magnetically equivalent nature of all
1
four of the xylylene protons in the H NMR spectrum.
Free rotation of the p-xylylenyl roof is possible because
of the large cavity size of these cyclophanes.
Cyclop h a n es w ith P olyfu n ction a l Micr oen vir on -
m en t. Introduction of multifunctionality into the micro-
environment of the cyclophane has several advantages.
It enhances the solubility of the cyclophane, creates a
hydrophilic cavity, and increases the complexing ability.
We focused on the synthesis of cyclophanes 21, 21a , 23,
and 24. Coupling of the dibromide 5b with 3,5-bis-
(mercaptomethyl)anisole (20) gave the cyclophane 21
(40%) (Scheme 5).
F igu r e 2. Unit cell packing of the cyclophane 1a .
tively, by two different routes. Treatment of 3c or 3g
with CH2N2 in THF afforded the cyclophane 3d or 3h .
The alternate method is to convert the cyclophane
carboxylic acids 3c and 3g into the acid chlorides using

Synthesis of Intra-Annular Cyclophanes
J . Org. Chem., Vol. 61, No. 15, 1996 5093
Sch em e 2
Sch em e 3
CPK space-filling model of cyclophane 21 are shown in
Figures 4, 5, and 6, respectively.
Similarly, coupling of the dibromide 5c with the dithiol
20 under identical conditions gave the cyclophane 21a .
The IR spectrum of 21a showed the carbonyl absorption
at 1715 cm-1
.
The 1H NMR and other spectral and
analytical data supported the structure 21a . Treatment
of the cyclophane 21 with SOCl2 in CH2Cl2 in the
presence of pyridine afforded the acid chloride intermedi-
ate, which on refluxing with methanol gave the cyclo-
phane 21a . All attempts to demethylate 21 to the
corresponding diphenolic cyclophane failed. The thio
linkage in the cyclophane 21 was cleaved by reagents
such as HI or BBr3. Hence, our attention was diverted
to the coupling reaction of the phenolic dithiol 2211
prepared from 3,5-bis(bromomethyl)anisole.13 Coupling
of dithiol 22 with dibromide 5c in benzene and in the
presence of KOH in ethanol afforded the cyclophane 23
in 40% yield. Hart et al.11 have used the same thiol, and
a similar report has been cited in the literature. The IR
spectrum of cyclophane 23 showed a carbonyl absorption
at 1720 cm-1 in addition to the hydroxyl absorption at
The high polarity and high melting point of 21 could
be due to the presence of two carboxylic acid functional-
ities. The IR spectrum of 21 showed a carbonyl absorp-
1
tion at 1710 cm-1. The H NMR spectrum of 21 showed
two singlets of eight protons at δ 3.58 and 3.62 for the
SCH2 and CH2S protons, respectively, and a six-proton
1
singlet at δ 3.69 for the methoxy protons. The H NMR
spectrum of cyclophane 21, in addition to the aromatic
protons, displayed broad singlets at δ 6.60 (HA) of four
protons and δ 6.76 of two protons (HB) for the aromatic
protons derived from the thiol unit. The shielding effect
observed for the HA and HB protons of cyclophane 21
could be due to the electron-releasing effect of the
methoxy group. In the 13C NMR spectrum, the carboxyl
carbon appeared at δ 159.51. In the mass spectrum, the
molecular ion appeared at m/e 997. Although all of these
data are consistent with a monomeric structure, the
dimeric structure 21 received support from XRD stud-
ies.12 The Ortep diagram, stereoview of the unit cell, and
3500-3300 cm-1
. Spectral and analytical data also
supported the proposed structure 23. Our attempts to
connect the OH groups in cyclophane 23 using p-xylylene
R,R′-dibromide failed, and polymeric materials were
obtained. However, coupling of the cyclophane 23 with
1 equiv of o-xylylene R,R′-dibromide in K2CO3/DMF under
high dilution afforded the cyclophane 24 (50%), which
has a cage structure. The 1H NMR spectrum of 24
showed four singlets of eight protons each at δ 3.20 and
3.70 and a four-proton singlet at δ 5.00, in addition to
the aromatic protons. Another independent method had
been developed for the cyclophane 24 using the dibromide
5c and tetrathiol 31.
(12) The authors have deposited atomic coordinates for the cyclo-
phanes 1a and 21 with the Cambridge Crystallographic Data Centre.
The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, U.K.
(13) Boekelheide, V.; Griffin, R. W., J r. J . Org. Chem. 1969, 34, 1960.

5094 J . Org. Chem., Vol. 61, No. 15, 1996
Kannan et al.
Sch em e 4
Sch em e 5
Cyclop h a n es w ith a Ca ge Str u ctu r e. The cyclo-
phanes with a cage structure14 may imitate some of the
naturally occurring haemocyanin systems.15 The copper
atoms in haemocyanins are separated by a distance of
3.55A. We next studied the synthesis of cyclophanes with
a cage structure and with a cavity size of about 4 Å
bearing polar functional groups able to bind metal ions
such as Cu2+. Such cyclophanes can accommodate two
Cu atoms and should support electron transfer reactions
inside the microenvironment. Toward the synthesis of
caged cyclophanes, the tetrathiol 29 was prepared from
o-xylylene R,R′-dibromide. Reaction of o-xylylene R,R′-
dibromide with 2 equiv of ethyl 5-hydroxyisophthalate
(25) in the presence of K2CO3 in DMF gave the tetraester
26 in 80% yield. Reduction of 26 with LAH followed by
treatment with SOCl2 gave the dichloride 28, which was
converted into tetrathiol 29 in 70% yield by the conven-
Coupling of the tetrathiol 29 with 2 equiv of dibromide
5a in benzene in the presence of KOH in ethanol afforded
the cyclophane 24a in 35% yield. Similarly, coupling of
tetrathiol 29 under identical condition with 2 equiv of
dibromide 5b gave the cyclophane dicarboxylic acid 24b
in 40% yield (Scheme 7). In the IR spectrum, cyclophane
24b displayed a carbonyl absorption at 1720 cm-1. In
the 1H NMR spectrum, two singlets of eight protons each
for SCH2 and CH2S were observed at δ 3.31 and 3.70 and
the OCH2 protons appeared as a singlet at δ 5.01.
Further, in the aromatic region, HA protons appeared at
δ 6.93 as a singlet of two protons and another singlet of
four protons (HB) appeared at δ 6.30. The protons meta
and para to the COOH group in the m-terphenyl unit
appeared as a doublet at δ 7.37 (Hm) and as a triplet (Hp)
at δ 7.52, respectively. The carboxylic acid proton
appeared as a broad singlet at δ 12.6. In the 13C NMR
spectrum, the carbonyl carbon appeared at δ 170.343.
The structure 24b received further support from its mass
spectrum and elemental analysis. Coupling of 29 with
2 equiv of 5c afforded the cyclophane 24 in 35% yield, as
evidenced by the spectral and analytical data. However,
the coupling of 29 with 5 afforded colorless material
insoluble in most of the usual solvents, which prevented
1
tional route11 (Scheme 6). The H NMR spectrum of 29
displayed a four-proton triplet at δ 1.70 for the SH
protons, an eight-proton doublet at δ 3.50 for the CH2S
protons, and broad singlets at δ 4.95 and 6.60 of four and
six protons, respectively. The o-xylylenyl protons ap-
peared as a multiplet at δ 7.00-7.25.
(14) Rajakumar, P.; Kannan, A. Tetrahedron Lett. 1993, 34, 8317.
(15) Sharma, P.; Vigee, G. S. Inorg. Chim. Acta 1984, 88, 29.

Synthesis of Intra-Annular Cyclophanes
J . Org. Chem., Vol. 61, No. 15, 1996 5095
Treatment of 2 equiv of NaH with ethylene glycol in
DMF gave the disodium salt. Reaction of the salt with
the acid chloride, derived from m-terphenyl carboxylic
acid 4b and SOCl2, gave ethylene 1,2-bis(4,4′′-dimethyl-
1,1′:3′,1′′-terphenyl-2′-carboxylate) (30) in 35% yield. The
diester 30 can be purified to a colorless crystalline solid
on a silica gel column. Treatment of 30 with 4 equiv of
NBS in CCl4 in the presence of benzoyl peroxide afforded
the tetrabromide 31 in 60% yield (Scheme 8).
The tetrabromide 31 can be purified only by crystal-
lization because it decomposes on silica gel. Coupling of
31 with 1 equiv of 29 under the usual conditions afforded
cyclophane 32 in 35% yield (Scheme 7). Cyclophane 32,
in its IR spectrum, showed an ester carbonyl at 1725
1
cm-1, and in its H NMR spectrum, four two-proton AB
quartets were observed at δ 3.66, 3.77 and at δ 3.85, 3.96
for the SCH2 and CH2S protons. The OCH2 protons
appeared as a singlet at δ 3.72. The HA and HB protons
of 32 appeared as singlets of two protons and four
protons, respectively, at 6.95 and 6.60. The Hp protons
appeared at δ 7.52 as a triplet and the Hm protons
appeared at δ 7.35 as a doublet. In the 13C NMR
spectrum, the carbonyl carbon appeared at δ 169.78. The
proposed structure 32 received further support from mass
spectral and elemental analyses. However, coupling of
R,R′-bis[3,5-bis(mercaptomethyl)phenoxyl-p-xylene with
the dibromide 5a , 5b , or 5c gave only polymeric
products.
F or m a tion of th e Sod iu m Sa lt of Cyclop h a n es 3c,
21, a n d 24b. Encouraged by the synthesis of novel
cyclophanes via a simple route, our attention turned to
the formation of sodium salts of some of the cyclophane
carboxylic acids as well as host-guest complexes.
F igu r e 4. Ortep diagram of the cyclophane 2I.
F igu r e 5. Stereoview of the unit cell of cyclophane 2l.
its characterization by physical methods. Cyclophane 24
has also been obtained from 24b by treatment with SOCl2
in CH2Cl2 in the presence of pyridine followed by reflux-
ing in methanol. Similarly, treatment of cyclophane 24a
with n-BuLi at -78 °C followed by bubbling with CO2
resulted in the formation of 24b.

5096 J . Org. Chem., Vol. 61, No. 15, 1996
Kannan et al.
Sch em e 6
appeared at δ 6.87 and 6.47 as triplet and doublet,
respectively. The shielding effect clearly indicates the
formation of the COO- anion. Furthermore, the solubil-
ity of the cyclophane carboxylic acid 24b improved after
the formation of the disodium salt.
(c) Disod iu m Sa lt of th e Cyclop h a n e 21. XRD
analysis of the cyclophane 21 revealed that the cyclo-
phane has an elliptical shape with the two carboxylic acid
groups facing each other. X-ray analysis indicated the
presence of hydrogen bonding between the two COOH
groups and that the OCH3 groups were farther apart.
Treatment of dicarboxylic acid 21 with NaOMe in DMSO-
d6 showed remarkable changes in the 1H NMR spectrum.
The SCH2 and CH2S proton signals appeared at δ 3.58
and 3.62 in both the cyclophane 21 and its disodium salt.
The Hp and Hm protons of the m-terphenyl system
appeared at δ 6.88 and 6.45 as a triplet and a doublet
for the sodium salt of the cyclophane 21. However, the
1H NMR spectrum of cyclophane 21 displayed a triplet
at δ 7.37 for the Hp protons and the Hm protons merged
in the aromatic region (δ 7.16-7.25). Upon formation of
the disodium salt, the chemical shifts of Hp and Hm are
shielded and show a clear triplet and doublet pattern for
Hp and Hm, respectively. The OCH3 protons appeared
in the same region (δ 3.69) in both the cyclophane 21 and
its disodium salt.
F igu r e 6. CPK space filling model of cyclophane 2l.
(a ) Sod iu m Sa lt of Cyclop h a n e 3c. Cyclophane
carboxylic acid 3c was treated with dry NaOMe in
anhydrous DMSO-d6. The 1H NMR spectrum showed
remarkable differences in the chemical shifts of some of
the protons. Although no distinct change was seen with
respect to the SCH2 and CH2S protons, the OCH2 protons
showed a significant shift. In cyclophane 3c, the OCH2
protons appeared at δ 5.20, while in the sodium salt they
appeared as a singlet at δ 4.60. This suggests that the
OCH2 protons are proximate to the COOH group. An-
other remarkable change in the aromatic region is the
appearance of the Hp and Hm protons at δ 6.87 as a triplet
and at δ 6.47 as a doublet. However, in cyclophane 3c
these protons appeared as multiplets at δ 7.40-7.42 (Hm)
and as a broad singlet at δ 7.44-7.48 (Hp). These
changes suggest the formation of the sodium salt.
(b) Disod iu m Sa lt of th e Cyclop h a n e 24b. The
disodium salt of cyclophane 24b could be even more
interesting. The cyclophane carboxylic acid 24b reacts
with NaOMe in DMSO-d6, showing remarkable changes
F or m a tion of Host-Gu est Com p lex of th e Cyclo-
p h a n e 21. The ethanol complex of cyclophane 21 upon
X-ray analysis, was found to have one ethanol molecule
in the cavity. The ethanol complex of cyclophane 21 was
also found to be thermally stable. The ethanol molecule
remained as a guest in the host 21 even after heating
over a water bath under vacuum for many hours.
Apparently, cyclophane 21 trapped the ethanol molecule
during its formation (ethanol is used as the solvent for
the coupling reaction). Ethanol binds to the COOH
groups present in the cyclophane 21. Further host-guest
complexation studies of other cyclophanes and metal ion
chelation with the cyclophanes are under investigation.
1
in the H NMR spectrum. The SCH2 and CH2S protons
of the disodium salt appeared at δ 3.30 and 3.70 as
singlets. However, the OCH2 protons appeared at δ 4.60
for the sodium salt instead of at δ 5.00. Possibly, the
COO- anion has a long-range shielding effect on the
OCH2 protons. The HA protons of 24b were not affected
by the formation of the sodium salt which indicates that
these protons are farther from the COOH group. How-
ever, the Hp and Hm protons underwent dramatic changes.
In cyclophane 24b, these appeared at δ 7.52 and 7.37 as
a triplet and doublet, but in the disodium salt, they
X-r a y Cr ysta llogr a p h y Stu d y of Cyclop h a n e 1a .
Crystals from chloroform belong to orthorhombic space

Synthesis of Intra-Annular Cyclophanes
J . Org. Chem., Vol. 61, No. 15, 1996 5097
Sch em e 7
Sch em e 8
groups form parallel hydrogen bonds. The molecules are
held in the lattice by van der Waals interactions.
Con clu sion s
This paper describes the synthesis of cyclophanes with
macrocyclic cavities and with functionalized micro-
environments. Moreover, the synthesis of cyclophanes
with polyfunctional microenvironments is described.
Introduction of such functionality creates a hydrophilic
cavity and improves the solubility of the cyclophanes. It
also increases the complexing ability and chelating
capacity of the cyclophanes. Finally, the synthesis of
cyclophanes with a cage structure is described. Such
cyclophanes are new, and our current work entails the
modification of the synthesis of cyclophanes with a cage
structure to make those that can bind two Cu(I) ions. We
have also reported the formation of the sodium salt of
some of these cyclophanes, one of which has been used
for host-guest complexation. We are further investigat-
ing metal ion chelation and host-guest complexation
with these reported cyclophanes.
group Pna21 with a ) 11.721(3), b ) 15.778(2), and c )
20.879(4) Å, V ) 3861(4) Å3, Z ) 4, DC ) 1.19 g/cm3, Cu
KR (λ ) 1.5418 Å) radiation (graphite monochromated),
µ ) 1.54 mm-1, and F(000) ) 1480. The structure was
refined to a final R ) 0.070, Rw ) 0.077 for 2172
reflection, I > 3σ(I). Three water molecules are caught
inside the cavity, and they form hydrogen bonds with
each other, forming a triangular plane. The molecule
possesses a noncollapsible rigid cavity of size approxi-
mately 7.5 × 8.5 Å2 measured between opposite arms of
the molecule. The molecules are packed in the unit cell
by van der Waals interactions.
Exp er im en ta l Section
Gen er a l P r oced u r es. All melting points are uncorrected.
1H NMR spectra were recorded at 400 and 90 MHz. 13C NMR
spectra were recorded at 100.6 MHz. J values are reported
in hertz. Tetrahydrofuran was distilled from Na/benzophe-
none ketyl before use, DMF was distilled over calcium hydride,
ethylenediamine and pyridine were distilled over sodium
hydroxide, and thionyl chloride was freshly distilled prior to
use. n-Butyllithium (15% solution in n-hexane) purchased
from MERCK-Schuchardt was used. Mass spectra were
measured at 25 or 70 eV. FAB mass spectra were obtained
at the Michigan State University mass spectrometry facility.
Column chromatography was carried out with SiO2 (silica gel,
ACME, 100-200 mesh). The organic extracts of crude prod-
ucts were dried over anhydrous magnesium sulfate.
X-r a y Cr ysta llogr a p h ic Stu d y of Cyclop h a n e 21.
Crystals from chloroform belong to monoclinic space
group A2/a with a ) 26.868(3), b ) 16.373(2), and c )
13.025(3) Å, â ) 90.38(2)°, V ) 5730(2) Å3, Z ) 4, DC
)
1.20 g/cm3, Cu KR (λ ) 1.5418 Å) radiation (graphite
monochromated), µ ) 1.91 mm-1, and F(000) ) 2248. The
structure was refined to R ) 0.072, Rw ) 0.079 for 2246
reflections I > 3σ(I). The molecule contains ethanol as
the solvent of crystallization. The hydroxyl proton of the
solvent molecule forms a hydrogen bond with one of the
carbonyl oxygen atoms. The whole molecule has a center
of inversion, and the oxygen atoms of the two carboxylic
4,4′′-Dim eth yl-1,1′:3′,1′′-ter p h en yl (4). To a Grignard
reagent, prepared by refluxing a mixture of 4-bromotoluene
(14.0 g, 82.5 mmol) and Mg (2.2 g, 90 mmol) in dry THF (250

5098 J . Org. Chem., Vol. 61, No. 15, 1996
Kannan et al.
mL) under nitrogen, was added dropwise a solution of 2,6-
dichloroiodobenzene (7.5 g, 27.5 mmol) in THF (50 mL), and
the mixture was refluxed for 3 h. After removal of THF under
reduced pressure, the reaction mixture was treated with dilute
HCl (10% v/v, 75 mL) and extracted with ether. The extracts
were washed successively with water and aqueous NaHCO3,
dried (MgSO4), and concentrated in vacuo. The crude product
was chromatographed on silica gel eluting with n-hexane to
give crystalline 4 (5.7 g, 80%): mp 112 °C; 1H NMR (CCl4, 90
MHz) δ 2.30 (s, 6 H, CH3), 7.00 (m, 12 H, ArH); 13C NMR
(CDCl3, 25 MHz) δ 20.90, 125.80, 125.90, 127.16, 127.24,
129.30, 129.70, 137.30, 141.90; MS, m/e (relative intensity) 258
(M+, 100).
2′-Br om o-4,4′′-d im eth yl-1,1′:3′,1′′-ter p h en yl (4a ). The
same procedure used for 4 was followed except that prior to
aqueous quench bromine (0.88 g, 5.5 mmol in 50 mL in CCl4)
was added dropwise to the reaction mixture and stirred for
30 min. The workup was as above except for sodium bisulfite
wash (2 × 50 mL) to remove excess bromine gave 4a (70%):
mp 118 °C; 1H NMR (CCl4, 90 MHz) δ 2.30 (s, 6 H, CH3), 7.00-
7.25 (m, 11 H); MS, m/e (relative intensity) 338 (M+, 100), 336
(M+, 100), 257 (80), 242 (80), 226 (20).
4,4′′-Dim eth yl-1,1′:3′,1′′-ter ph en yl-2′-car boxylic Acid (4b).
A procedure similar to that for 4 was followed, the reaction
was quenched with CO2 (dry CO2 was bubbled into the solution
continuously for 10 h), and the resulting solution was treated
with cold HCl (10% v/v, 40 mL). Usual workup followed by
chromatographic separation on silica gel using CH2Cl2-hexane
(3:2) gave 4b (70%): mp 174 °C; IR (KBr) 1695 cm-1; 1H NMR
(CDCl3, 90 MHz) δ 2.30 (s, 6 H, CH3), 7.00-7.25 (m, 11 H);
MS, m/e (relative intensity) 302 (M+, 100), 285 (60), 269 (10),
242 (20).
converted to the corresponding dibromide 5a (75%): mp 110
°C; 1H NMR (CCl4, 90 MHz) δ 4.30 (s, 4 H, CH2Br), 7.00-7.25
(m, 11 H).
4,4′′-Bis(b r om om et h yl)-1,1′:3′,1′′-t er p h en yl-2′-ca r b ox-
ylic Acid (5b). According to the general procedure A, di-
methylterphenyl 4 was converted to the corresponding dibro-
mide 5b (65%): mp 165 °C; IR (KBr) 1695 cm-1 1H NMR
;
(CDCl3, 90 MHz) δ 4.35 (s, 4 H, CH2Br), 7.00-7.25 (m, 11 H).
Meth yl 4,4′′-Bis(br om om eth yl)-1,1′:3′,1′′-ter p h en yl-2′-
ca r boxyla te (5c). According to the general procedure A,
dimethylterphenyl 4 was converted to the corresponding
dibromide 5c (60%): mp 110 °C; IR (KBr) 1720 cm-1; 1H NMR
(CDCl3, 90 MHz) δ 3.35 (s, 3 H, CO2CH3), 4.50 (s, 4 H, CH2Br),
7.20-7.55 (m, 11 H).
Gen er a l P r oced u r e B. P r ep a r a tion of th e Diester s 6,
6a , 12, a n d 16. A mixture of methyl p-hydroxybenzoate (63
mmol), the dibromide (27.7 mmol), and potassium carbonate
(15 g) in anhydrous DMF (60 mL) was stirred under nitrogen
for 48 h at 60 °C. The reaction mixture was poured into water
(250 mL) and stirred. The resulting precipitate was filtered,
washed with water, and dissolved in CH2Cl2 (350 mL). The
organic layer was washed with NaOH solution (5% w/v, 2 ×
50 mL), dried (MgSO4), and evaporated to yield the corre-
sponding diester.
Diester 6. According to the general procedure B, diester 6
(85%) was prepared from the dibromide 5: mp 184 °C; IR (KBr)
1720 cm-1; 1H NMR (CDCl3, 90 MHz) δ 3.70 (s, 6 H, CO2Me),
4.90 (s, 4 H, OCH2), 6.70 and 7.70 (ABq, J ) 9, 8 H), 7.20-
7.50 (m, 12 H). Anal. Calcd for C36H30O6: C, 77.41; H, 5.41.
Found: C, 77.32; H, 5.29.
Diester 6a . According to the general procedure B, diester
6a (75%) was prepared from the dibromide 5a : mp 185 °C; IR
(KBr) 1720 cm-1 1H NMR (CDCl3, 90 MHz) δ 3.70 (s, 6 H,
;
Met h yl 4,4′′-Dim et h yl-1,1′:3′,1′′-t er p h en yl-2′-ca r b ox-
yla te (4c). To a stirred suspension of acid 4b (3.0 g, 10 mmol)
in CH2Cl2 (120 mL) containing pyridine (0.80 g, 10 mmol) was
added a solution of thionyl chloride (1.69 g, 10 mmol) in CH2Cl2
(20 mL). The mixture was stirred at room temperature for
12 h and evaporated to dryness to give a pale yellow residue.
Methanol (50 mL) was added to the residue, and then the
solution was refluxed for 4 h. The reaction mixture was
evaporated to dryness, extracted with CH2Cl2 (2 × 150 mL),
and dried (MgSO4). The crude product obtained after the
removal of the solvent was chromatographed on silica gel
eluting with CH2Cl2-hexane (1:3) to give 4c (80%): mp 109
CO2Me), 4.90 (s, 4 H, OCH2), 6.80 and 7.75 (ABq, J ) 9, 8 H),
7.20-7.50 (m, 11 H). Anal. Calcd for C36H29BrO6: C, 67.83;
H, 4.58. Found: C, 67.93; H, 4.69.
Diester 12. According to the general procedure B, diester
12 (90%) was prepared from o-xylylene R,R′-dibromide: mp
142 °C; IR (KBr) 1715 cm-1; 1H NMR (CDCl3, 90 MHz) δ 3.85
(s, 6 H, CO2Me), 5.20 (s, 4 H, OCH2), 7.00 and 8.05 (ABq, J )
9, 8 H), 7.35-7.50 (m, 4 H); MS, m/e (relative intensity) 406
(M+, 100).
Diester 16. According to the general procedure B, the
diester 16 (80%) was prepared from p-xylylene R,R′-dibro-
1
°C; IR (KBr) 1720 cm-1; H NMR (CDCl3, 90 MHz) δ 2.35 (s,
1
mide: mp 128 °C; IR (KBr) 1715 cm-1; H NMR (CDCl3, 90
6 H, CH3), 3.35 (s, 3 H, CO2CH3), 7.15-7.50 (m, 11 H); MS,
m/e (relative intensity) 316 (M+, 50), 285 (100), 242 (25), 165
(10), 58 (50).
MHz) δ 3.85 (s, 6 H, CO2CH3), 5.20 (s, 4 H, OCH2), 7.00 and
8.05 (ABq, J ) 9, 8 H), 7.20 (s, 4 H); MS, m/e (relative
intensity) 406 (M+, 100).
Alter n a te P r oced u r e for 4c. To a stirred solution of the
acid 4b (1.5 g, 5 mmol) in THF (10 mL) was added an ethereal
solution of diazomethane [generated from diazald (2.14 g, 10
mmol), water (5 mL), ether (30 mL), and aqueous NaOH (5 N,
6 mL)]. The reaction mixture was stirred at room temperature
for 30 min, and the solvent was allowed to evaporate. The
crude product was chromatographed on silica gel eluting with
CH2Cl2-hexane (1:3) to give ester 4c quantitatively.
Gen er a l P r oced u r e A. NBS Br om in a tion of th e m -
Ter p h en yls. Freshly recrystallized NBS (92 mmol) was
added in five-six equal portions 6 h apart to a solution of
compound (44 mmol) in CCl4 (350 mL) heated at reflux; each
addition was immediately followed by the addition of a few
milligrams of benzoyl peroxide. After 40 h of total reaction
time at reflux, the mixture was cooled and the precipitated
succinimide was removed by filtration. The solvent was
removed, and the residue was chromatographed (SiO2) and
recrystallized from a CH2Cl2-hexane mixture.
Gen er a l P r oced u r e C. Red u ction of th e Diester s 6,
6a , 12, a n d 16. To a solution of the diester (13.8 mmol) in
dry THF (300 mL) was added in portions LAH (0.59 g, 17.3
mmol) at room temperature. The reaction mixture was stirred
at reflux for 6 h, poured into Na2SO4‚10H2O (10 g), and stirred.
It was then digested on a steam bath (20 min) and filtered.
The inorganic residue was further extracted (Soxhlet) with
THF (200 mL). The combined THF fractions upon evaporation
gave the alcohol, purified by recrystallization from a minimum
volume of THF-MeOH (3:1).
Diol 7. According to the general procedure C, diol 7 (90%)
was obtained from the diester 6. For 7: mp 208 °C; IR (KBr)
1
3500-3300 cm-1; H NMR (DMSO-d6, 400 MHz) δ 4.50 (d, J
) 6.5, 4 H, CH2OH), 5.10 (t, J ) 6.5, 2 H, OH, exchanges with
D2O), 5.20 (s, 4 H, OCH2), 7.04 and 7.29 (ABq, J ) 8, 8 H),
7.60 and 7.84 (ABq, J ) 8, 8 H), 7.71 (d, J ) 3.6, 2 H), 7.73
(m, 1 H), 7.97 (m, 1 H); MS, m/e 485 (M+ - H2O). Anal. Calcd
for C34H30O4: C, 81.26; H, 6.01. Found: C, 81.35; H, 6.14.
Diol 7a . According to the general procedure C, diol 7a
(85%) was obtained from the diester 6a . For 7a : mp 210 °C;
4,4′′-Bis(br om om eth yl)-1,1′:3′,1′′-ter p h en yl (5). Accord-
ing to the general procedure A, dimethylterphenyl 4 was
converted to the corresponding dibromide 5 (80%): mp 108
°C; 1H NMR (CCl4, 90 MHz) δ 4.30 (s, 4 H, CH2Br), 7.00-7.25
(m, 12 H); 13C NMR (CDCl3, 25 MHz) δ 33.10, 126.20, 126.50,
127.60, 127.80, 129.50, 129.90, 137.20, 141.30. Anal. Calcd
for C20H16Br2: C, 57.72; H, 3.88. Found: C, 57.66; H, 3.98.
1
IR (KBr) 3500-3300 cm-1; H NMR (DMSO-d6, 400 MHz) δ
4.50 (d, J ) 6.5, 4 H, CH2OH), 5.10 (t, J ) 6.5, 2 H, OH,
exchanges with D2O), 5.20 (s, 4 H, OCH2), 7.31 and 7.60 (ABq,
J ) 8, 8 H), 7.62 and 7.86 (ABq, J ) 8, 8 H), 7.73 (m, 2 H),
7.75 (m, 1 H); MS, m/e (relative intensity) 565 (MH+ - H2O,
100). Anal. Calcd for C34H29BrO4: C, 70.23; H, 5.02. Found:
C, 70.37; H, 5.18.
2′-Br om o-4,4′′-bis(br om om eth yl)-1,1′:3′,1′′-ter ph en yl (5a).
According to the general procedure A, dimethylterphenyl 4 was

Synthesis of Intra-Annular Cyclophanes
J . Org. Chem., Vol. 61, No. 15, 1996 5099
Diol 13a . According to the general procedure C, diol 13a
(90%) was obtained from the diester 12. For 13a : mp 187 °C;
g, 2.5 mmol) in ethanol (95%, 800 mL). After addition was
complete, the mixture was stirred for an additional 8 h and
then evaporated to dryness. The crude product was chromato-
graphed to give the corresponding cyclophane.
1
IR (KBr) 3500-3300 cm-1; H NMR (CDCl3, 90 MHz) δ 4.50
(s, 4 H, CH2OH), 5.16 (bs, 1 H, OH), 5.20 (s, 4 H, OCH2), 6.90-
7.10 (m, 4 H), 7.20-7.35 (m, 8 H).
Cyclop h a n e 1a . Coupling of the dichloride 8 with o-xylene-
R,R′-dithiol16 (9) (general procedure F) and purification on silica
gel with CH2Cl2-hexane (1:1) as the eluent afforded the
cyclophane 1a (70%): mp 206 °C; 1H NMR (CDCl3, 400 MHz)
δ 3.60 (s, 4 H, SCH2), 3.65 (s, 4 H, CH2S), 5.25 (s, 4 H, OCH2),
6.80 and 7.15 (ABq, J ) 8, 8 H), 7.09-7.13 (m, 2 H), 7.17-
7.21 (m, 2 H), 7.40 and 7.55 (ABq, J ) 8, 8 H), 7.56-7.59 (m,
3 H), 7.67 (m, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 33.19
(SCH2), 35.93 (CH2S), 69.01 (OCH2), 115.64, 125.52, 126.92,
127.01, 127.74, 128.16, 128.95, 129.67, 129.80, 130.35, 136.35,
136.74, 140.70, 141.67, 156.59 (15 Ar carbons). Anal. Calcd
for C42H36O2S2: C, 72.21; H, 5.69. Found: C, 79.16; H, 5.76.
Cyclop h a n e 1b. Coupling of dichloride 8a with dithiol 9
(general procedure F) and purification on silica gel with
CH2Cl2-hexane (1:1) as the eluent afforded the cyclophane 1b
(60%): mp 202 °C; 1H NMR (CDCl3, 400 MHz) δ 3.60 (s, 4 H,
SCH2), 3.65 (s, 4 H, CH2S), 5.25 (s, 4 H, OCH2), 6.73 and 7.08
(ABq, J ) 8, 8 H), 7.02-7.06 (m, 2 H), 7.10-7.14 (m, 2 H),
7.33 and 7.48 (ABq, J ) 8, 8 H), 7.49-7.52 (m, 3 H); 13C NMR
(CDCl3, 100.6 MHz) δ 33.25 (SCH2), 36.00 (CH2S), 69.09
(OCH2), 115.71, 125.59, 126.98, 127.07, 127.82, 128.23, 129.00,
129.72, 129.87, 130.41, 136.39, 136.79, 140.78, 141.74, 156.65
(15 Ar carbons); MS (FAB) (m-nitrobenzyl alcohol matrix), m/e
716 (MH+). Anal. Calcd for C42H35BrO2S2: C, 70.48; H, 4.92.
Found: C, 70.61; H, 4.99.
Diol 17. According to the general procedure C, diol 17 (90%)
was obtained from the diester 16. For 17: mp 165 °C; IR (KBr)
3500-3300 cm-1 1H NMR (CDCl3, 90 MHz) δ 4.50 (s, 4 H,
;
CH2OH), 5.10 (bs, 1 H, OH), 5.20 (s, 4 H, OCH2), 7.15-7.45
(m, 12 H).
Gen er a l P r oced u r e D. Con ver sion of th e Diol in to th e
Dich lor id e. To a stirred suspension of the diol (9.76 mmol)
in CH2Cl2 (120 mL) containing pyridine (1.54 g, 19.5 mmol)
was added a solution of thionyl chloride [2.3 g, 19.5 mmol in
CH2Cl2 (20 mL)]. The mixture was stirred at rt for 12 h and
then washed with water (3 × 100 mL). The organic layer was
dried (MgSO4), and upon evaporation, a pale yellow solid was
obtained. Recrystallization of the solid from CH2Cl2-hexane
afforded the corresponding pure dichloride.
Dich lor id e 8. According to the general procedure D,
dichloride 8 (95%) was obtained from the diol 7. For 8: mp
1
164 °C; H NMR (CCl4, 90 MHz) δ 4.40 (s, 4 H, CH2Cl), 4.90
(s, 4 H, OCH2), 6.70-6.80 (m, 4 H), 7.00-7.50 (m, 16 H). Anal.
Calcd for C34H28Cl2O2: C, 75.69; H, 5.22. Found: C, 75.92;
H, 5.33.
Dich lor id e 8a . According to the general procedure D,
dichloride 8a (85%) was obtained from the diol 7a . For 8a :
1
mp 166 °C; H NMR (CDCl3, 90 MHz) δ 4.40 (s, 4 H, CH2Cl),
4.90 (s, 4 H, OCH2), 6.80-7.00 (m, 4 H), 7.10-7.60 (m, 15 H).
Dich lor id e 14. According to the general procedure D,
dichloride 14 (95%) was obtained from the diol 13. For 14:
Cyclop h a n e 1c. Coupling of the dichloride 8 with p-xylene-
R,R′-dithiol17 (10) (general procedure F) followed by purification
on silica gel with CH2Cl2-hexane (1:1) as the eluent afforded
the cyclophane 1c (60%): mp 155 °C; 1H NMR (CDCl3, 400
MHz) δ 3.49 (s, 4 H, SCH2), 3.55 (s, 4 H, CH2S), 5.25 (s, 4 H,
OCH2), 6.75 and 7.05 (ABq, J ) 8, 8 H), 7.16 (s, 4 H), 7.38 and
1
mp 98 °C; H NMR (CDCl3, 90 MHz) δ 4.50 (s, 4 H, CH2Cl),
5.10 (s, 4 H, OCH2), 6.80-7.00 (m, 4 H), 7.20-7.40 (m, 8 H).
Dich lor id e 18. According to the general procedure D,
dichloride 18 (90%) was obtained from the diol 17. For 18:
1
mp 92 °C; H NMR (CDCl3, 90 MHz) δ 4.50 (s, 4 H, CH2Cl),
7.55 (ABq, J ) 8, 8 H), 7.46-7.53 (m, 3 H), 7.61 (m, 1 H); 13
C
5.15 (s, 4 H, OCH2), 6.95-7.30 (m, 12 H).
NMR (CDCl3, 100.6 MHz) δ 35.10 (SCH2), 35.39 (CH2S), 69.63
(OCH2), 115.78, 125.74, 127.07, 127.39, 127.66, 129.03, 129.09,
29.79, 129.97, 136.42, 136.73, 140.67, 141.57, 156.96 (14 Ar
carbons). Anal. Calcd for C42H36O2S2: C, 79.21; H, 5.69.
Found: C, 79.34; H, 5.74.
Gen er a l P r oced u r e E. Syn th esis of Dith iols 11, 15, 19,
a n d 20. A stirred solution of dihalide (6.2 mmol) and thiourea
(0.95 g, 12.4 mmol) in THF (60 mL) was heated at reflux for
12 h. The mixture was cooled, and the precipitated isothio-
uronium salt was filtered and dried. The salt was dissolved
in H2O-THF (1:2 v/v, 180 mL) under nitrogen, and to this
solution was added KOH (0.52 g, 9.4 mmol). The mixture was
heated under nitrogen at reflux for 12 h, and then cooled, and
the resulting solution was carefully quenched with minimum
amount of dilute HCl (2 N). The solvent was removed under
vacuum, and the crude product was chromatographed (SiO2)
to give the corresponding dithiol.
Cyclop h a n e 1d . Coupling of the dichloride 8a with dithiol
10 (general procedure F) and purification on silica gel with
CH2Cl2-hexane (1:1) as the eluent afforded the cyclophane 1d
(55%): mp 153 °C; 1H NMR (CDCl3, 400 MHz) δ 3.50 (s, 4 H,
SCH2), 3.55 (s, 4 H, CH2S), 5.25 (s, 4 H, OCH2), 6.75 and 7.05
(ABq, J ) 8, 8 H), 7.16 (s, 4 H), 7.38 and 7.53 (ABq, J ) 8, 8
H), 7.43-7.51 (m, 3 H), MS (FAB) (m-nitrobenzyl alcohol
matrix), m/e 716 (MH+). Anal. Calcd for C42H35BrO2S2: C,
70.48; H, 4.92. Found: C, 70.59; H, 4.99.
Cyclop h a n e 2a . Coupling of the dichloride 8 with dithiol
11 (general procedure F) followed by purification on silica gel
with CH2Cl2-hexane (3:2) as the eluent afforded the cyclo-
phane 2a (30%): mp 175 °C; 1H NMR (CDCl3, 400 MHz) δ
3.55 (s, 4 H, SCH2), 3.58 (s, 4 H, CH2S), 5.20 (s, 4 H, OCH2),
6.74 and 7.04 (ABq, J ) 8, 8 H), 7.15 (d, J ) 8, 6 H), 7.24-
7.27 (m, 4 H), 7.40-7.55 (m, 12 H), 7.64 (m, 1 H), 7.66 (m, 1
H); 13C NMR (CDCl3, 100.6 MHz) δ 34.55 (SCH2), 35.60 (CH2S),
69.79 (OCH2), 115.78, 125.57, 125.77, 126.01, 126.57, 126.87,
127.01, 127.41, 127.63, 129.18, 129.41, 129.71, 129.89, 130.77,
136.82, 136.98, 140.06, 140.90, 141.70, 157.22 (20 Ar carbons);
MS (FAB) (m-nitrobenzyl alcohol matrix), m/e 788 (MH+).
Anal. Calcd for C54H44O2S2: C, 82.20; H, 5.62. Found: C,
82.33; H, 5.69.
4,4′′-Bis(m er ca p tom eth yl)-1,1′:3′,1′′-ter p h en yl (11). Ac-
cording to the general procedure E, dithiol 11 (60%, SiO2,
CH2Cl2-hexane, 1:3) was obtained from the dibromide 5. For
1
11: mp 112 °C; H NMR (CDCl3, 90 MHz) δ 1.60 (t, J ) 7.5,
2 H, SH), 3.60 (d, J ) 7.5, 4 H, CH2SH), 6.90-7.35 (m, 12 H);
MS, m/e (relative intensity) 323 (M+, 20), 306 (90), 289 (100).
Dith iol 15. According to the general procedure E, dithiol
15 (60%, SiO2, CH2Cl2-hexane, 1:2) was obtained from the
dichloride 14. For 15: mp 56 °C; 1H NMR (CDCl3, 90 MHz) δ
1.60 (t, J ) 7.5, 2 H, SH), 3.60 (d, J ) 7.5, 4 H, CH2SH), 5.10
(s, 4 H, OCH2), 6.80-7.00 (m, 4 H), 7.20-7.40 (m, 8 H).
Dith iol 19. According to the general procedure E, dithiol
19 (60%, SiO2, CH2Cl2-hexane, 1:2) was obtained from the
dichloride 18. For 19: mp 54 °C; 1H NMR (CDCl3, 90 MHz) δ
1.60 (t, J ) 7.5, 2 H, SH), 3.55 (d, J ) 7.5, 4 H, CH2SH), 5.20
(s, 4 H, OCH2), 6.90-7.30 (m, 12 H).
Cyclop h a n e 2b. Coupling of the dichloride 8a with dithiol
11 (general procedure F) followed by purification on silica gel
with CH2Cl2-hexane (3:2) as the eluent gave the cyclophane
2b (25%): mp 177 °C; 1H NMR (CDCl3, 400 MHz) δ 3.55 (s, 4
H, SCH2), 3.58 (s, 4 H, CH2S), 5.20 (s, 4 H, OCH2), 6.78 and
7.08 (ABq, J ) 8, 8 H), 7.19 (d, J ) 8, 6 H), 7.28 (m, 4 H),
7.45-7.59 (m, 12 H), 7.68 (m, 1 H); MS (FAB) (m-nitrobenzyl
3,5-Bis(m er ca p tom eth yl)a n isole (20). According to the
general procedure E, dithiol 20 (60%, SiO2, CH2Cl2-hexane,
1:2) was obtained from 3,5-bis(bromomethyl)anisole. For 20:
1H NMR (CDCl3, 90 MHz) δ 1.75 (t, J ) 7.7, 2 H), 3.65 (d, J )
7.7, 4 H, CH2SH), 3.70 (s, 3 H, OCH3), 6.70 (bs, 2 H), 6.85 (bs,
1 H).
Gen er a l P r oced u r e F . Assem blin g Cyclop h a n es 1a -
d , 2a ,b, 3a -h , 21, 21a , a n d 23. A solution containing
equimolar amounts (1 mmol) of the appropriate dibromide and
the dithiol in nitrogen-degassed benzene (100 mL) was added
dropwise over 8-10 h to a well-stirred solution of KOH (0.14
(16) (a) Kotz, A. Chem. Ber. 1900, 33, 729. (b) Autenrieth, W.;
Hennings, R. Chem. Ber. 1901, 34, 1772.
(17) Kulka, M. Can. J . Chem. 1956, 34, 1093.

5100 J . Org. Chem., Vol. 61, No. 15, 1996
Kannan et al.
alcohol matrix), m/e 867 (MH+). Anal. Calcd for C54H43
BrO2S2: C, 74.73; H, 4.99. Found: C, 74.87; H, 5.07.
-
cyclophane 3g (60%): mp 200 °C; IR (KBr) 1710 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 3.60 (s, 4 H, SCH2), 3.65 (s, 4 H, CH2S),
5.20 (s, 4 H, OCH2), 6.80 and 6.85 (ABq, J ) 8.7, 8 H), 7.00
and 7.20 (ABq, J ) 8, 8 H), 7.16 (s, 4 H), 7.40-7.42 (m, 2 H),
7.44-7.46 (m, 1 H), 12.60 (bs, 1 H, CO2H).
Cyclop h a n e 3h . Coupling of the dibromide 5c with the
dithiol 19 (general procedure F) followed by purification on
silica gel with CH2Cl2-hexane (1:1) as the eluent gave the
cyclophane 3h (70%): mp 205 °C; IR (KBr) 1720 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 3.10 (s, 3 H, CO2CH3), 3.43 (s, 4 H, SCH2),
3.72 (s, 4 H, CH2S), 5.00 (s, 4 H, OCH2), 6.80 and 6.90 (ABq,
J ) 8, 8 H), 7.25-7.35 (m, 12 H), 7.50-7.53 (m, 3 H). Anal.
Calcd for C44H38O4S2: C, 76.05; H, 5.51. Found: C, 76.23; H,
5.61.
Con ver sion of Cyclop h a n es 1b, 1d , 2b, 3b, or 3f to 1a ,
1c, 2a , 3a , or 3e. To a solution of cyclophane 1b, 1d , 2b, 3b,
or 3f (0.2 mmol) in dry THF (10 mL) was added n-butyllithium
(1.6 M, 0.27 mL) at -78 °C under nitrogen. After the reaction
mixtured was stirred for 3 h at -78 °C, the reaction was
quenched with cold HCl (10% v/v, 3 mL), and the resulting
solution was extracted with CH2Cl2 (2 × 20 mL) and dried
(MgSO4). The reaction mixture after usual workup afforded
the cyclophanes 1a , 1c, 2a , 3a , or 3e in 80, 85, 80, 70, and
80% yields, respectively.
Con ver sion of Cyclop h a n es 3b or 3f to 3c or 3g. To a
solution of cyclophane 3b or 3f (0.2 mmol) in dry THF (10 mL)
was added n-butylithium (1.6 M, 0.20 mL) at -78 °C under
nitrogen. The mixture was stirred under nitrogen at that
temperature for 3 h, and the reaction was quenched with CO2
(bubbling dry CO2 gas into the solution for 3 h). After usual
workup and column chromatographic separation, the com-
pound was found to be 3c or 3g (70%, 60%), respectively.
Con ver sion of Cyclop h a n es 3c or 3g to 3d or 3h . To a
stirred suspension of cyclophane 3c or 3g (0.2 mmol) in CH2Cl2
(120 mL) containing pyridine (0.01 g, 0.1 mmol) was added a
solution of thionyl chloride (0.01 g, 1 mmol) in CH2Cl2 (20 mL).
The mixture was stirred at room temperature for 3 h and then
evaporated to dryness. Methanol (10 mL) was added to the
residue, and then the solution was refluxed for 4 h. The
reaction mixture was extracted with CH2Cl2 (2 × 20 mL) after
the removal of methanol, washed with water (20 mL), and
dried (MgSO4). The crude product after purification was found
to be identical with the cyclophane 3d or 3h (85 or 80%),
respectively.
Cyclop h a n e 3a . Coupling of the dibromide 5 with the
dithiol 15 (general procedure F) followed by purification on
silica gel with CH2Cl2-hexane (1:1) as the eluent yielded the
cyclophane 3a (70%): mp 206 °C; 1H NMR (CDCl3, 400 MHz)
δ 3.60 (s, 4 H, SCH2), 3.65 (s, 4 H, CH2S), 5.20 (s, 4 H, OCH2),
6.81 and 7.15 (ABq, J ) 8, 8 H), 7.09-7.13 (m, 2 H), 7.17-
7.21 (m, 2 H), 7.40 and 7.50 (ABq, J ) 8, 8 H), 7.55-7.58 (m,
3 H), 7.65 (m, 1 H); 13C NMR (CDCl3, 100.6 MHz) δ 33.19
(SCH2), 35.93 (CH2S), 69.01 (OCH2), 115.64, 125.52, 126.92,
127.01, 127.74, 128.16, 128.95, 129.67, 129.80, 130.35, 136.33,
136.74, 140.70, 141.67, 156.59 (15 Ar carbons). Anal. Calcd
for C42H36O2S2: C, 79.21; H, 5.69. Found: C, 79.37; H, 5.78.
Cyclop h a n e 3b. Coupling of the dibromide 5a with the
dithiol 15 (general procedure F) afforded the cyclophane 3b
(65%, SiO2, CH2Cl2-hexane, 1:1): mp 203 °C; 1H NMR (CDCl3,
400 MHz) δ 3.60 (s, 4 H, SCH2), 3.65 (s, 4 H, CH2S), 5.25 (s, 4
H, OCH2), 6.73 and 7.08 (ABq, J ) 8, 8 H), 7.02-7.06 (m, 2
H), 7.10-7.14 (m, 2 H), 7.33 and 7.48 (ABq, J ) 8, 8 H), 7.49-
7.52 (m, 3 H); 13C NMR (CDCl3, 100.6 MHz) δ 33.25 (SCH2),
36.00 (CH2S), 69.09 (OCH2), 115.71, 125.59, 126.98, 127.07,
127.92, 128.23, 129.00, 129.72, 129.87, 130.41, 136.39, 136.79,
140.78, 141.74, 156.64 (15 Ar carbons). Anal. Calcd for
C42H35BrO2S2: C, 70.48; H, 4.92. Found: C, 70.59; H, 4.97.
Cyclop h a n e 3c. Coupling of the dibromide 5b with the
dithiol 15 (general procedure F) afforded the cyclophane 3c
(70%, SiO2 CH2Cl2-hexane, 7:3): mp 201 °C; IR (KBr) 1710
1
cm-1; H NMR (CDCl3, 400 MHz) δ 3.60 (s, 4 H, SCH2), 3.65
(s, 4 H, CH2S), 5.20 (s, 4 H, OCH2), 6.81 and 6.86 (ABq, J )
8.7, 8 H), 7.00 and 7.20 (ABq, J ) 8, 8 H), 7.30-7.33 (m, 4 H),
7.40-7.42 (m, 2 H), 7.44-7.48 (m, 1 H), 12.60 (bs, 1 H, CO2H);
13C NMR (CDCl3, 100.6 MHz) δ 35.22 (SCH2), 35.65 (CH2S),
67.84 (OCH2), 115.16, 128.29, 128.35, 128.42, 128.66, 128.98,
129.09, 130.40, 131.02, 133.02, 134.65, 137.71, 138.46, 139.50,
156.17 (15 Ar carbons), 169.69 (CO2H).
Cyclop h a n e 3d . Coupling of the dibromide 5c with the
dithiol 15 (general procedure F) followed by purification on
silica gel with CH2Cl2-hexane (1:1) as the eluent afforded the
cyclophane 3d (75%): mp 208 °C; IR (KBr) 1720 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 3.10 (s, 3 H, CO2CH3), 3.43 (s, 4 H, SCH2),
3.72 (s, 4 H, CH2S), 5.03 (s, 4 H, OCH2), 6.82 and 6.94 (ABq,
J ) 8, 8 H), 7.28-7.40 (m, 12 H), 7.49-7.53 (m, 3 H); 13C NMR
(CDCl3, 100.6 MHz) δ 34.11 (SCH2), 36.44 (CH2S), 51.81 (CO2-
CH3), 68.10 (OCH2), 114.82, 128.38, 128.53, 128.86, 129.42,
129.54, 130.30, 130.79, 134.26, 135.04, 138.14, 139.30, 140.12,
157.78 (14 Ar carbons), 169.87 (CO2CH3); MS (FAB) (m-
nitrobenzyl alcohol matrix), m/e 695 (MH+). Anal. Calcd
C44H38O4S2: C, 76.05; H, 5.51. Found: C, 76.19; H, 5.67.
Cyclop h a n e 3e. Coupling of the dibromide 5 with the
dithiol 19 (general procedure F) followed by purification on
silica gel with CH2Cl2-hexane (1:1) as the eluent afforded the
cyclophane 3e (65%): mp 198 °C; 1H NMR (CDCl3, 400 MHz)
δ 3.49 (s, 4 H, SCH2), 3.55 (s, 4 H, CH2S), 5.25 (s, 4 H, OCH2),
6.75 and 7.05 (ABq, J ) 8, 8 H), 7.16 (s, 4 H), 7.38 and 7.55
(ABq, J ) 8, 8 H), 7.46-7.56 (m, 3 H), 7.61 (m, 1 H); 13C NMR
(CDCl3, 100.6 MHz) δ 35.10 (SCH2), 35.39 (CH2S), 69.63
(OCH2), 115.78, 125.74, 127.07, 127.39, 127.66, 129.03, 129.09,
129.79, 129.97, 136.42, 136.73, 140.67, 141.57, 156.96 (14 Ar
carbons). Anal. Calcd for C42H36O2S2: C, 79.21; H, 5.69.
Found: C, 79.37; H, 5.68.
Alter n a te P r oced u r e for th e Con ver sion of th e Cyclo-
p h a n es 3c or 3g to 3d or 3h . To a stirred solution of
cyclophane 3c or 3g (0.3 mmol) in THF (5 mL) was added an
ethereal solution of diazomethane [generated from diazald
(0.12 g, 1 mmol), water (0.5 mL), ether (3 mL), and aqueous
NaOH (5 N, 0.6 mL)]. After usual workup of the reaction
mixture, followed by chromatographic separation, the cyclo-
phane 3d or 3h was afforded in quantitative yield.
Cyclop h a n e 21. Coupling of the dibromide 5b with the
dithiol 20 followed by purification on silica gel with 5 drops of
MeOH in 50 mL of CH2Cl2 as the eluent afforded cyclophane
1
21 (40%): mp 252 °C; Ir (KBr) 1710 cm-1; H NMR (DMSO-
d6, 400 MHz) δ 3.58 (s, 8 H, SCH2), 3.62 (s, 8 H, CH2S), 3.69
(s, 6 H, OCH3), 6.60 (s, 2 H), 6.76 (s, 4 H), 7.16-7.25 (m, 20
H), 7.37 (t, J ) 8.34, 2 H), 12.62 (bs, 2 H); 13C NMR (DMSO-
d6, 100.6 MHz) δ 34.87 (SCH2), 35.25 (CH2S), 55.05 (OCH3),
112.93, 122.65, 127.65, 128.40, 128.63, 128.70, 128.90, 130.05,
137.10, 137.45, 137.85, 139.68 (12 Ar carbons), 159.50 (CO2H);
MS (FAB) (m-nitrobenzyl alcohol matrix), m/e 997 (MH+).
Cyclop h a n e 21a . Coupling of the dibromide 5c with the
dithiol 20 followed by purification on silica gel with CH2Cl2-
hexane (1:1) as the eluent gave the cyclophane 21a (50%): mp
261 °C; IR (KBr) 1715 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.58
(s, 8 H, SCH2), 3.62 (s, 8 H, CH2S), 3.69 (s, 6 H, OCH3), 3.72
(s, 6 H, CO2CH3), 6.60 (s, 2 H), 6.76 (s, 4 H), 7.16-7.25 (m, 20
H), 7.37 (t, J ) 8.14, 2 H); 13C NMR (CDCl3, 100.6 MHz) δ
34.87 (SCH2), 35.25 (CH2S), 55.05 (OCH3), 68.01 (CO2CH3),
112.93, 122.65, 127.65, 128.40, 128.63, 128.70, 128.90, 130.05,
137.10, 137.45, 137.85, 139.68, (12 Ar carbons), 161.05 (CO2Me);
MS (FAB) (m-nitrobenzyl alcohol matrix), m/e 1025 (MH+).
Anal. Calcd for C62H56O6S4: C, 72.63; H, 5.50. Found: C,
72.51; H, 5.48.
Cyclop h a n e 3f. Coupling of the dibromide 5a with the
dithiol 19 (general procedure F) followed by purification on
silica gel with CH2Cl2-hexane (1:1) as the eluent afforded the
1
cyclophane 3f (70%): mp 195 °C; H NMR (CDCl3, 400 MHz)
δ 3.50 (s, 4 H, SCH2), 3.55 (s, 4 H, CH2S), 5.25 (s, 4 H, OCH2),
6.75 and 7.05 (ABq, J ) 8, 8 H), 7.16 (s, 4 H), 7.38 and 7.53
(ABq, J ) 8, 8 H), 7.43-7.51 (m, 3 H); 13C NMR (CDCl3, 100.6
MHz) δ 35.12 (SCH2), 35.40 (CH2S), 69.69 (OCH2), 115.79,
125.74, 127.09, 127.41, 127.66, 129.03, 129.11, 129.80, 129.99,
136.44, 136.74, 140.67, 141.57, 156.99 (14 Ar carbons). Anal.
Calcd for C42H35BrO2S2: C, 70.48; H, 4.92. Found: C, 70.57;
H, 4.99.
Cyclop h a n e 3g. Coupling of the dibromide 5b with the
dithiol 19 (general procedure F) followed by purification on
silica gel with CH2Cl2-hexane (7:3) as the eluent gave the

Synthesis of Intra-Annular Cyclophanes
J . Org. Chem., Vol. 61, No. 15, 1996 5101
Con ver sion of Cyclop h a n e 21 to 21a . To a stirred
suspension of cyclophane 21 (0.1 g, 0.1 mmol) in CH2Cl2 (120
mL) containing pyridine (0.02 g, 0.2 mmol) was added a
solution of thionyl chloride (0.024 g, 0.2 mmol) in CH2Cl2 (20
mL). The mixture was stirred at room temperature for 4 h
and then evaporated to dryness. Methanol (10 mL) was added
to the residue, and then the solution was refluxed for 4 h. The
reaction mixture was evaporated to dryness, extracted with
CH2Cl2 (2 × 20 mL), washed with water (2 × 20 mL), and dried
(MgSO4). Evaporation of CH2Cl2 gave the crude product
which, after purification on silica gel, was found to be cyclo-
phane 21a (0.065 g, 65%).
reflux for 12 h and then cooled, and the reaction was carefully
quenched with a minimum amount of dilute HCl (2 N, 20 mL).
The solvent was removed under vacuum, and the crude
product was chromatographed [SiO2, CH2Cl2-hexane (1:1)] to
1
give 29 (1.82 g, 70%) as colorless solid: mp 58 °C; H NMR
(CDCl3, 90 MHz) δ 1.70 (t, J ) 7.6, 4 H, SH), 3.50 (d, J ) 7.6,
8 H, CH2SH), 4.95 (s, 4 H, OCH2), 6.60 (bs, 6 H), 7.00-7.25
(m, 4 H); MS, m/e (relative intensity) 474 (M+, 1.8), 438 (1),
407 (1), 290 (13), 289 (42), 288 (43), 257 (12), 256 (17), 255
(72), 105 (100). Anal. Calcd for C24H26O2S4: C, 60.72; H, 5.52.
Found: C, 60.83; H, 5.49.
Gen er a l P r oced u r e G. Cou p lin g of Tetr a th iol w ith
Tetr a br om id e or 2 Equ iv of Dibr om id e. A solution
containing tetrathiol 29 (0.235 g, 0.5 mmol) and the appropri-
ate dibromide (1 mmol) or tetrabromide (0.5 mmol) in nitrogen-
degassed benzene (100 mL) was added dropwise over 8-10 h
to a well-stirred solution of KOH (140 mg, 2.5 mmol) in
aqueous ethanol (95%, 800 mL). After addition was complete,
the mixture was stirred for an additional 8 h and then
evaporated to dryness. The crude product obtained after usual
workup was purified by column chromatography.
Cyclop h a n e 24. The coupling of 2 equiv of 5c with 1 equiv
of 29 (general procedure G) afforded the cyclophane 24 (35%)
after purification on silica gel with CH2Cl2-hexane (1:1) as
the eluent. For 24: mp 285 °C (dec); IR (KBr) 1725 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 3.20 (s, 8 H, SCH2), 3.70 (s, 14 H,
CO2CH3 and CH2S), 5.00 (s, 4 H, OCH2), 6.35 (s, 4 H), 7.00 (s,
2 H), 7.20-7.50 (m, 26 H); 13C NMR (CDCl3, 100.6 MHz) δ
34.39 (SCH2), 35.74 (CH2S), 51.70 (CO2CH3), 67.80 (OCH2),
114.60, 121.90, 128.05, 128.26, 128.47, 128.99, 129.03, 129.26,
133.77, 135.13, 137.56, 139.01, 139.55, 139.79, 158.59 (15 Ar
carbons), 169.52 (CO2CH3); MS (FAB) (m-nitrobenzyl alcohol),
m/e 1099 (MH+). Anal. Calcd for C68H58O6S4: C, 74.29; H,
5.23. Found: C, 74.23; H, 5.37.
Cyclop h a n e 23. Coupling of the dibromide 5c with 3,5-
bis(mercaptomethyl)phenol (22)11 followed by purification on
silica gel with 5% MeOH in CH2Cl2 as the eluent afforded the
cyclophane 23 (40%): mp 272 °C; IR (KBr) 3500-3300, 1720
1
cm-1; H NMR [CDCl3/CD3OD (4:1), 400 MHz] δ 3.60 (s, 8 H,
SCH2), 3.64 (s, 8 H, CH2S), 3.68 (s, 6 H, CO2CH3), 6.71 (s, 2
H), 6.87 (s, 4 H), 7.19-7.20 (m, 20 H), 7.39 (t, J ) 7.95, 2 H).
r,r′-Bis[3,5-bis(d ica r beth oxy)p h en oxy]-o-xylen e (26).
A mixture of diethyl 5-hydroxyisophthalate18 (25), o-xylylene
R,R′-dibromide (7.31 g, 27.7 mmol), and potassium carbonate
(15 g) in anhydrous DMF (60 mL) was stirred under nitrogen
for 60 h at room temperature. The mixture was poured into
water (250 mL) and stirred. The colorless solid obtained was
filtered, washed with water (3 × 50 mL), and dissolved in
CH2Cl2 (350 mL). This solution was washed with aqueous
NaOH (5% w/v, 2 × 50 mL), dried (MgSO4), and evaporated
to give a residue which, upon purification by column chroma-
tography (SiO2) with hexane-CH2Cl2 (2:3) as the eluent,
afforded tetraester 26 (16.09 g, 80%): mp 82 °C; Ir (KBr) 1710
cm-1; 1H NMR (CDCl3, 90 MHz) δ 1.25 (t, J ) 7.1, 12 H, CH3),
4.30 (q, J ) 7.1, 8 H, CO2CH2), 5.20 (s, 4 H, OCH2), 7.30-7.50
(m, 4 H), 7.75 (bs, 4 H), 8.25 (bs, 2 H). Anal. Calcd for
C32H34O10: C, 66.43; H, 5.92. Found: C, 66.29; H, 5.89.
r,r′-Bis[3,5-bis(h ydr oxym eth yl)ph en oxy]-o-xylen e (27).
To a solution of tetraester 26 (8.0 g, 13.8 mmol) in dry THF
(300 mL) was added in portions at room temperature LAH
(1.18 g, 34.6 mmol) suspended in THF (30 mL). The mixture
was stirred at reflux for 6 h. The reaction mixture was then
poured into Na2SO4‚10H2O (10g) and stirred. It was then
digested on a steam bath (30 min) and filtered. The inorganic
residue was extracted (Soxhlet) with THF (200 mL). The
combined THF fractions upon evaporation gave the tetra-
alcohol 27 (4.55 g, 90%), which was purified by recrystalliza-
tion from a minimum volume of THF-MeOH (3:1): mp 130
°C; IR (KBr) 3540, 3340-3320 cm-1; 1H NMR (DMSO-d6, 400
MHz) δ 4.50 (s, 8 H, CH2OH), 5.15 (bs, 8 H, OCH2 and OH),
6.90 (bs, 4 H), 6.92 (bs, 2 H), 7.40-7.43 (m, 2 H), 7.56-7.59
(m, 2 H); MS, m/e (relative intensity) 374 (M+ - 2 H2O, 1),
257 (3), 239 (49), 209 (45), 105 (82), 104 (100). Anal. Calcd
for C24H26O6: C, 70.23; H, 6.38. Found: C, 70.21; H, 6.45.
r,r′-Bis[3,5-bis(ch lor om eth yl)p h en oxy]-o-xylen e (28).
To a stirred suspension of the tetraalcohol 27 (4.0 g, 9.76 mmol)
in CH2Cl2 (120 mL) containing pyridine (3.08 g, 39 mmol) was
added a solution of thionyl chloride (4.6 g, 39.0 mmol) in
CH2Cl2 (20 mL). The mixture was stirred at room temperature
for 12 h and then washed with water (3 × 100 mL). The
organic layer was dried (MgSO4) and evaporated to yield the
tetrachloride 28 (4.30 g, 90%): mp 85 °C; 1H NMR (CDCl3, 90
MHz) δ 4.40 (s, 8 H, CH2Cl), 4.90 (s, 4 H, OCH2), 6.85 (bs, 6
H), 7.40-7.45 (m, 2 H), 7.50-7.65 (m, 2 H); MS, m/e (relative
intensity) 484 (M+, 19), 482 (12), 332 (16), 330 (26), 328 (27),
310 (18), 308 (27), 295 (100), 294 (24), 293 (92). Anal. Calcd
for C24H22ClO4: C, 59.53; H, 4.58. Found: C, 59.65; H, 4.39.
r,r′-Bis[3,5-bis(m er captom eth yl)ph en oxy]-o-xylen e (29).
A stirred solution of the tetrachloride 28 (3.0 g, 6.2 mmol) and
thiourea (1.89 g, 24.8 mmol) in THF (60 mL) was heated at
reflux for 12 h. The mixture was cooled, and the precipitated
isothiouronium salt was filtered and dried (6.15 g, 76%). This
salt was dissolved in H2O-dioxane (1:2 v/v, 180 mL) under
nitrogen, and to this solution was added ethylenediamine (1.13
g, 18.8 mmol). The mixture was heated under nitrogen at
Cyclop h a n e 24a . The coupling of 2 equiv of 5a with 1
equiv of 29 (general procedure G) afforded the cyclophane 24a
(35%) after purification on silica gel with CH2Cl2-hexane (1:
1) as the eluent. For 24a : mp 260 °C (dec); 1H NMR (CDCl3,
400 MHz) δ 3.40 (s, 8 H, SCH2), 3.70 (s, 8 H, CH2S), 5.00 (s, 4
H, OCH2), 6.20 (s, 4 H), 7.10 (s, 2 H), 7.10-7.40 (m, 26 H); 13
C
NMR (CDCl3, 100.6 MHz) δ 35.04 (SCH2), 35.88 (CH2S), 66.76
(OCH2), 114.32, 121.62, 126.84, 127.51, 127.74, 128.56, 129.27,
129.65, 130.27, 134.75, 137.44, 139.59, 140.49, 143.42, 158.31
(15 Ar carbons); MS (FAB) (m-nitrobenzyl alcohol matrix), m/e
1141 (MH+).
Cyclop h a n e 24b . The coupling of 2 equiv of 5b with 1
equiv of 29 (general procedure G) afforded the cyclophane 24b
(40%) after purification on silica gel with 10 drops of MeOH
in CH2Cl2 (250 mL) as the eluent. For 24b: mp 232 °C; IR
1
(KBr) 1720 cm-1; H NMR (DMSO-d6, 400 MHz) δ 3.30 (s, 8
H, SCH2), 3.70 (s, 8 H, CH2S), 5.00 (s, 4 H, OCH2), 6.30 (s, 4
H), 6.93 (s, 2 H), 7.15 and 7.26 (ABq, J ) 8.8, 16 H), 7.31-
7.33 (m, 4 H), 7.37 (d, J ) 8, 4 H), 7.52 (t, J ) 8.8, 2 H), 12.6
(bs, 2 H, COOH); 13C NMR (DMSO-d6, 100.6 MHz) δ 34.40
(SCH2), 35.23 (CH2S), 67.80 (OCH2), 114.48, 121.90, 128.23,
128.52, 128.56, 128.69, 129.19, 129.23, 135.01, 135.49, 138.08,
138.77, 138.86, 139.95, 158.41 (15 Ar carbons), 170.34 (CO2H);
MS (FAB) (m-nitrobenzyl alcohol matrix), m/e 1071 (MH+).
Anal. Calcd for C66H54O6S4: C, 73.99; H, 5.08. Found: C,
73.78; H, 5.05.
Con ver sion of Cyclop h a n e 24a to 24b. To a stirred
solution of cyclophane 24a (0.12 g, 0.1 mmol) in dry THF (10
mL) was added n-BuLi (1.6 M, 0.2 mL) at -78 °C under
nitrogen. The mixture was stirred under nitrogen at that
temperature for 3 h and heated with CO2 (bubbling dry CO2
gas into the solution for 3 h), and the reaction was quenched
with dilute HCl (2 N, 2 mL). The reaction mixture was
extracted with CH2Cl2, washed with water, and dried (MgSO4).
The crude product after purification on silica gel column was
found to be cyclophane 24b.
Con ver sion of Cyclop h a n e 24b to 24. To a stirred
suspension of cyclophane 24b (540 mg, 0.05 mmol) in CH2Cl2
(120 mL) containing pyridine (0.01 g, 0.1 mmol) was added a
solution of thionyl chloride (0.012 g, 0.1 mmol) in CH2Cl2 (20
mL). The mixture was stirred at rt for 5 h and then
evaporated to give a pale yellow solid as a residue. Methanol
(18) Collman, J . P.; Brawman, J . I.; Fitzgerald, J . P.; Hampton, P.
D.; Naruta, Y.; Sparapancy, J . W. J . Am. Chem. Soc. 1988, 110, 3477.

5102 J . Org. Chem., Vol. 61, No. 15, 1996
Kannan et al.
(10 mL) was added to the residue and then refluxed for 4 h.
The reaction mixture was evaporated to dryness, extracted
with CH2Cl2, washed with water, and dried (MgSO4). The
residue obtained after evaporation of the solvent on purifica-
tion using silica gel gave cyclophane 24.
Con ver sion of Cyclop h a n e 23 to 24. A solution of
cyclophane 23 (100 mg, 0.1 mmol) and o-xylylene dibromide
(27 mg, 0.1 mmol) in nitrogen-degassed dry DMF (30 mL) was
added dropwise over a period of 4-5 h to a well-stirred
suspension of K2CO3 (1.0 g) in dry DMF (50 mL). The reaction
mixture was stirred for an additional hour and evaporated to
dryness under reduced pressure. Purification of the residue
on silica gel by chromatography afforded the cyclophane 24
in 50% yield.
20), 329 (25), 285 (100), 269 (5). Anal. Calcd for C44H38O4:
C, 83.78; H, 6.07. Found: C, 83.69; H, 5.98.
Tetr a br om id e 31. Freshly prepared NBS (1.43 g, 8 mmol)
was added in four equal portions 6 h apart to a solution of
ester 30 (1.25 g, 2 mmol) in CCl4 (100 mL) heated at reflux,
each addition being followed by a few milligrams of benzoyl
peroxide. The mixture was cooled and filtered to remove the
succinimide. The solvent was evaporated from the filtrate, and
the residue was recrystallized from CH2Cl2-hexane (2:3) to
give the tetrabromide 31 (1.14 g, 60%): mp 202 °C; IR (KBr)
1
1735 cm-1; H NMR (CDCl3, 90 MHz) δ 3.50 (s, 4 H, OCH2),
4.40 (s, 8 H, CH2Br), 7.00-7.50 (m, 22 H). Anal. Calcd for
C44H34Br4O4: C, 55.84; H, 3.62. Found: C, 55.84; H, 3.68.
Cyclop h a n e 32. Coupling of 1 equiv of 31 with 1 equiv of
29 afforded cyclophane 32 (35%) after purification on silica
gel with CH2Cl2-hexane (1:1) as the eluent. For 32: mp 295
Eth ylen e 1,2-Bis(4,4′′-d im eth yl-1,1′:3′,1′′-ter p h en yl-2′-
ca r boxyla te) (30). To a stirred suspension of acid 4b (3.0 g,
10 mmol) in CH2Cl2 (120 mL) containing pyridine (800 mg, 10
mmol) was added a solution of thionyl chloride (1.16 g, 10
mmol) in CH2Cl2 (20 mL). The mixture was stirred at rt for
12 h and then evaporated to dryness. The acid chloride thus
obtained was added in five-six equal portions to a stirred
solution of ethylene glycol (310 mg, 5 mmol) and NaH (60%,
400 mg, 10 mmol) in dry DMF (100 mL). The reaction mixture
was then stirred for 12 h at 70 °C. DMF was removed under
low pressure. To the residue was added crushed ice (200 g).
Then the resulting solution was extracted with CH2Cl2, and
the organic layer was washed with water, dried (MgSO4), and
evaporated in vacuo. The crude product was chromatographed
on silica gel using CH2Cl2-hexane (1:2) as the eluent to give
diester 30 (1.16g, 35%) as a colorless solid: mp 218 °C; IR
1
°C (dec); IR (KBr) 1725 cm-1; H NMR (DMSO-d8, 400 MHz)
δ 3.16 and 3.77 (ABq, J ) 10, 8 H, SCH2), 3.72 (s, 4 H, OCH2),
3.85 and 3.96 (ABq, J ) 16, 8 H, CH2S), 5.10 (s, 4 H, OCH2),
6.60 (s, 4 H), 6.95 (s, 2 H), 7.05 and 7.17 (ABq, J ) 8.8, 16 H),
7.20-7.25 (m, 4 H), 7.35 (d, J ) 8, 4 H), 7.52 (t, J ) 8.8, 2 H);
13C NMR (DMSO-d6, 100.6 MHz) δ 35.53 (SCH2), 35.79 (CH2S),
61.88 (OCH2), 68.86 (OCH2), 114.22, 121.99, 126.38, 126.62,
126.68, 128.02, 128.38, 128.59, 129.03, 129.55, 137.79, 138.99,
139.75, 139.96, 158.25 (15 Ar carbons), 169.77 (CO); MS (FAB)
(m-nitrobenzyl alcohol matrix), m/e 1097 (MH+). Anal. Calcd
for C68H56O6S4: C, 74.42; H, 5.14. Found: C, 74.29; H, 5.12.
Ack n ow led gm en t. We thank Prof. Harold Hart,
MSU, U.S.A. for the spectral data and discussion and
Prof. P. T. Manoharan, RSIC, IIT, Madras, for the
spectral data. A.K. and V.K. thank CSIR, New Delhi,
for financial support.
1
(KBr) 1735 cm-1; H NMR (CDCl3, 90 MHz) δ 2.20 (s, 12 H,
CH3), 3.50 (s, 4 H, OCH2), 6.75-7.15 (m, 22 H); 13C NMR
(CDCl3, 100.6 MHz) δ 21.11 (CH3), 61.88 (OCH2), 128.27,
128.58, 128.91, 129.34, 132.45, 137.14, 137.47, 140.33 (8 Ar
carbons), 169.18 (CO); MS, m/e (relative intensity) 630 (M+,
J O950957Y