Synthesis, separation, and structural analysis of planar chiral carboxy-substituted [2.2]metacyclophanes

Article abstract of DOI:10.1016/j.tet.2013.03.076

A two-step synthesis of carboxy-functionalized planar chiral [2.2]metacyclophanes from m-xylenes is described. Both transformative steps utilize LiNK metalation conditions (BuLi, KOt-Bu, TMP(H)) for m-xylene benzylic deprotonation with subsequent in situ

Full text of DOI:10.1016/j.tet.2013.03.076

Tetrahedron 69 (2013) 4285e4291
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis, separation, and structural analysis of planar chiral
carboxy-substituted [2.2]metacyclophanes
*
€
Marco Blangetti, Helge Muller-Bunz, Donal F. O’Shea
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step synthesis of carboxy-functionalized planar chiral [2.2]metacyclophanes from m-xylenes is
described. Both transformative steps utilize LiNK metalation conditions (BuLi, KOt-Bu, TMP(H)) for
m-xylene benzylic deprotonation with subsequent in situ oxidative CeC coupling. Inclusion of the car-
boxy substituents at either C4, or C4 and C14, renders the [2.2]metacyclophanes planar chiral and the
structural analysis of both substitution patterns has been achieved with X-ray crystallography and NMR
spectroscopy. The C4 mono- and C4/14 di-substituted carboxylic acid methyl ester racemates were
readily separated by analytical and preparative chiral HPLC and their inversion barriers measured in
heptanes at 373 K at 125.3 kJ/mol and 130.9 kJ/mol, respectively. The facile synthesis, separation, and
high inversion barriers of planar chiral [2.2]metacyclophanes present an opportunity for their in-
vestigation as chiral catalysts and ligands, which to date has yet to be explored.
Received 11 January 2013
Received in revised form 28 February 2013
Accepted 18 March 2013
Available online 22 March 2013
Keywords:
[2.2]Metacyclophane
Planar chirality
LiNK metalation
Structural analysis
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
to planar chiral [2.2]metacyclophanes, starting from inexpensive
commercially available substituted m-xylenes.9 Our strategy em-
The unique and intriguing properties of constrained [2.2]
cyclophanes has led to a continued interest in them since the first
report by Brown and Farthing in 1949.1 ‘Phane’ molecules template
ploys a selective LiNK benzylic metalation with an in situ oxidative
coupling reaction10 for both synthetic operations. In order to render
the [2.2]metacyclophane scaffold planar chiral, the symmetry plane
bisecting the cyclophane ring must be differentiated by sub-
stitution in either positions C4, or C4 and C14 (Fig.1), which renders
the original C2 symmetry lost and planar chirality created.4 In this
report, the synthesis, structural characterization, enantiomer sep-
aration, and configurational stability of potentially useful optically
active mono- and di-carboxy[2.2]metacyclophanes are described.
interactions between layered p-systems within constrained three-
dimensional architectures, and this unique feature has been ex-
tensively investigated and exploited.2 In this context, the [2.2]
paracyclophanes have seen a recent resurgence of interest, notably
as planar chiral scaffolds for asymmetric catalysis.3 Among the
other potential chiral cyclophane structures, the planar chirality of
[2.2]metacyclophanes has received scant attention, with the syn-
thesis of only a few chiral derivatives described.4 Thermodynamic
and kinetic studies have shown that for the [n.n]metacyclophanes,
only the most constrained [2.2]metacyclophanes have an inversion
barrier high enough to permit resolution of conformationally stable
enantiomers.5 However, few examples of optical resolution4a,6 and
crystal structure determination7 of planar chiral [2.2]meta-
cyclophanes have been reported to date.
A
B
We recently reported that challenging benzylic metalations can
be achieved with excellent regioselectivity by means of a mixed Li/
K metal TMP amide (LiNK metalation conditions) generated in situ
by the reagent triad BuLi/KOt-Bu/TMP(H).8 In the course of our
studies, aimed to exploit further synthetic applications of LiNK
metalation conditions, we described a two-step general approach
Fig. 1. Planar chiral [2.2]metacyclophanes.
2. Results and discussion
The preparation of planar chiral carboxy[2.2]metacyclophane
derivatives has been previously described in the literature via
lengthy multi-step approaches. For example, the synthesis of
[2.2]metacyclophane-4,14-dicarboxylic acid methyl ester (Fig. 1A,
R/R¼CO2CH3, Scheme 1 top) has been accomplished by conversion
* Corresponding author. Tel.: þ353 1 7162425; e-mail address: donal.f.oshea@
ucd.ie (D.F. O’Shea).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.076

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M. Blangetti et al. / Tetrahedron 69 (2013) 4285e4291
of the corresponding 4,14-dimethyl cyclophane, obtained as
a mixture with the 4,12-isomer after chloromethylation of toluene
followed by Wurtz coupling.4c,11 Bromomethylation and sub-
sequent Sommelet reaction led to the corresponding dialdehyde
derivatives, which were further transformed into a mixture of
diesters. Chromatography separation of the unwanted achiral 4,14-
isomer provided the target metacyclophane type A.4c,11 Mono-
substituted 4-carboxylic acid ester (Fig. 1B, R¼CO2CH3, Scheme 1
bottom) has been prepared by a six-step synthesis.4a In this case,
the metacyclophane skeleton was constructed by di-alkylation of
di-lithiated isophthalaldehyde bis-dithiane with 1-bromo-2,4-
bis(bromomethyl)benzene. Lithiumebromine exchange (of aryl-
bromide) followed by CO2 quench and esterification with diazo-
methane introduced an aryl ester group. Subsequent reductive
cleavage of dithianes with Raney Ni catalyst led to the targeted
cyclophane type B. Following saponification, both mono- and bis-
carboxy racemic mixtures could be resolved via their di-
astereomeric salts with (þ)-1-phenylethylamine.4a,12
LiNK metalation conditions with in situ oxidative coupling offers
a facile general approach to the [2.2]metacyclophanes.9 To access
carboxy-substituted planar chiral derivatives, two inexpensive
starting materials m-xylene and 2,4-dimethylbenzoic acid are re-
quired. From these two reagents, the C4 carboxy and C4/14 di-
carboxy derivatives were selected for synthesis as benchmark ex-
amples of this class of planar chiral scaffold.
2-Methyl metalation of 2,4-dimethylbenzoic acid 1 under LiNK
conditions9 for 15 min (additional equivalent of BuLi included
for deprotonation of the carboxylic acid) led to the dianion 2,
which underwent oxidative homocoupling after addition of
1,2-dibromoethane, leading to the corresponding 2,20-(ethane-
1,2-diyl)bis(4-methylbenzoic acid) 3 in 82% yield (Scheme 2).
Compound 3 represents a challenging substrate to selectively
achieve a di-benzylic metalation to generate the required tetra-
Scheme 1. Existing routes to substituent pattern types
metacyclophanes.
A
and
B
for [2.2]
Scheme 2. Iterative LiNK/oxidative coupling synthesis of [2.2]metacyclophane-4,14-
dicarboxylic acid 5 and corresponding dimethyl ester 6.

M. Blangetti et al. / Tetrahedron 69 (2013) 4285e4291
4287
Table 1
anionic species 4, as potential competing aryl and methylene met-
Crystal structure and relevant NMR spectral data for 6
alation sites also exist. In order to assess metalation selectivity
a deuteration study was first carried out prior to attempting ring
closure to the cyclophane. Upon metalation of 3 with LiNK conditions
(4:2:2 equiv of BuLi/KOt-Bu/TMP(H) at ꢀ78 ꢁC for 15 min) and
quenching with CD3OD, 2H NMR spectroscopy showed that selective
deuterium incorporation into both benzylic positions had been ach-
ieved to give 3-D2 without any aryl or ethylene bridge deuteration
detected. To effect ring closure to the cyclophane, metalation was
repeatedto provide4, whichwasringclosedwith1,2-dibromoethane
leading to 5rac in 35% yield after purification. Cyclophane 5 was sub-
sequently converted to the corresponding [2.2]metacyclophane-
4,14-dicarboxylic acid dimethyl ester 6rac with MeOH/HCl.
In a similar manner, we have previously shown that LiNK di-
benzylic metalation of substrate 7 and oxidative ring closure gener-
ates the planar chiral 4-carboxylic acid-substituted metacyclophane
8 (Scheme 3).9 Purification of the crude reaction mixture was ach-
ieved by column chromatography giving 8 in 39% yield as a racemic
mixture. Esterification of carboxylic acid 8rac was carried out in
MeOH/HCl under reflux to provide cyclophane 9rac in high yield.
Entry
Measurement
Data
ꢀ
1
2
3
4
5
6
7
8
Intra-annular distance (C8eC16)
A ring distortion from planarity
B ring distortion from planarity
Bond length C1eC2
2.66(1) A
7.7(1)ꢁ
7.7(4)ꢁ
ꢀ
1.574(2) A
109.94(12)ꢁ
ꢀ2.2(3)ꢁ
Angle C1eC2eC3
Torsion angle C3eC4eC18eO1
Torsion angle C15eC14eC20eO3
ꢀ9.5(2)ꢁ
Ha=Ha 0 chemical shifta
4.27 ppm
1.96 ppm
3.18 ppm
2.10 ppm
4.37 ppm
0
9
Hb=Hb chemical shifta
Hc=Hc 0 chemical shifta
0
10
11
12
Hd=Hd0 chemical shifta
He=He chemical shifta
a
In CDCl3.
adopt a co-planar conformation compared to the aromatic rings,
with a torsion angle C3eC4eC18eO1 of ꢀ2.2(3)ꢁ for the A ring
(entry 6) and C15eC14eC20eO3 of ꢀ9.5(2)ꢁ for the B ring (entry 7).
The two carbonyl groups C18eO1 and C20eO3 are thus aligned
0
facing toward the bridge protons Ha and Ha , which is confirmed in
solution by the 1H NMR chemical shift of 4.27 ppm for Ha and
upfield shift of 1.96 ppm for Hb (entries 8 and 9). This contrasts with
the Hc and Hd nuclei (Dd Hc/d¼1.08 ppm) sited on the non-
substituted face of the molecule (entries 10, 11).
The C4 carboxylic substituted metacyclophane 8 was crystal-
lized at room temperature from an acetone solution into the tri-
clinic space group P-1.15 A summary of the X-ray crystal and 1H
NMR spectral data is shown in Table 2. The overall geometrical
Scheme 3. LiNK/oxidative coupling synthesis of 4-carboxy-[2.2]metacyclophanes 8
and 9.
In anticipation of future investigations into the ability of meta-
cyclophanes to act as chiral catalysts and ligands, efforts were made
to obtain solid-state structures and high-resolution NMR spectral
data. Metacyclophane 6 was crystallized by the slow, room-
temperature evaporation of a diethyl ether solution, into the or-
thorhombic space group Pna21,13 and analysis of the X-ray crystal
structure with selected 1H NMR spectral data are summarized in
Table 1.
Table 2
Crystal structure and relevant spectral NMR data for 8
The X-ray structure confirmed the expected stepwise anti con-
formation typical of the [2.2]metacyclophane scaffold.14 The char-
acteristic geometrical feature of a strained metacyclophane is the
out of plane bending of the aromatic rings into a boat con-
formation,5b represented for diester 6 with a deviation from pla-
narity of 7.7(1)ꢁ and 7.7(4)ꢁ for the A and B rings, respectively (Table
1, entries 2 and 3). The central ten-membered ring adopts a chair-
like conformation, where the two aromatic rings sit in parallel
planes, as confirmed by the high 1H NMR shielding of the two
equivalent He aromatic protons at 4.37 ppm (entry 12). The closest
Entry
Measurement
Data
ꢀ
1
2
3
4
5
6
7
8
9
Intra-annular distance (C8eC16)
A ring distortion from planarity
B ring distortion from planarity
Bond length C1eC2
2.63(8) A
7.7(3)ꢁ
7.2(4)ꢁ
1.569(3) A
110.54(15)ꢁ
16.6(3)ꢁ
4.38 ppm
1.86 ppm
4.36 ppm
4.33 ppm
ꢀ
ꢀ
approach of the two benzene rings to one another is 2.66(1) A, as
Angle C1eC2eC3
measured from C8 to C16 (entry 1). The saturated bond length
Torsion angle C3eC4eC18eO1
ꢀ
(1.574(2) A) of the cavity measured from C1 to C2 (entry 4), together
Ha chemical shifta
with the bond angle C1eC2eC3 of 109.94(12)ꢁ (entry 5) further
confirm the shortness of the bridge and its effect on the ring strain
and conformational rigidity of the molecular framework. Note-
worthy is the orientation of the two carboxymethyl groups, which
Hb chemical shifta
H
e0chemical shifta
10
He chemical shifta
a
In CDCl3.

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M. Blangetti et al. / Tetrahedron 69 (2013) 4285e4291
features of the metacyclophane 8 reflect the same architecture of
the diester 6, with a small 10-membered ring cavity defined by
The racemic mixtures of methyl esters 6 and 9 were analyzed by
analytical chiral HPLC, showing good to excellent separations on
four different chiral stationary phases (Fig. 4). Racemates 6 and 9
were resolved by semi-preparative chiral HPLC using a Chiralcel OD
column, and the absolute configuration of pure enantiomers was
assigned by comparison of the optical rotation with literature
data.6b,12
ꢀ
a methylene bridge of 1.569(3) A measured from C1 to C2, a bond
angle of 110.54(15)ꢁ and the intra-annular distance of 2.63(8) A
ꢀ
(Table 2, entries 1, 4, 5). The crystal structure again shows the
parallel alignment of the two non-planar aromatic rings (entries 2
and 3) refl0ected in the 1H NMR shielding of the two non-equivalent
He and He protons (entries 9 and 10).
The carboxylic group has a small torsion angle of 16.6(3)ꢁ for
C3eC4eC18eO1 (entry 6), causing an alignment of the CO group
with the C2 bridge protons Ha. This accounts for the significant
difference in chemical shift (Dd of 2.52 ppm) observed for pseu-
doequatorial Ha and pseudoaxial Hb 1H NMR resonances (entries 7
and 8). The unit cell contains both enantiomers forming hydrogen-
ꢀ
bonded chains with a typical O/H length of 1.79(9) A (Fig. 2).
Fig. 2. H-bonding in X-ray structure 8.
The spatial arrangement of the carboxylate groups in the 4- and
14-positions of the aryl rings is noteworthy, as the anti stepwise
conformation of the metacyclophane scaffold presents the two
Brønsted acid functional groups in a distinctive manner. As shown
in the frontal view of their X-ray structures, derivatives 6 and 8 both
show a differentiation of the two sides of the molecules with re-
spect to the vertical plane bisecting the metacyclophane ring (Fig. 3,
left). The carboxylate groups are pointing toward one side defining
coordinating site(s) of the molecule, with the other side behaving
as the chiral discriminator. Uniquely, the stepwise conformation
may offer a potential chiral environment for an asymmetric
transformation. Moreover, in the case of the disubstituted de-
rivative 6, the staggered conformation of the two aromatic rings
arranges the functional groups into different planes, with a distance
Fig. 4. Chiral HPLC separation of 6 (top) and 9 (bottom) over Chiralpak IA (black),
Chiralpak IB (red), Chiralpak AS-H (blue), and Chiralcel OJ-H (green) columns.
ꢀ
of 5.34 A as measured from the two carbonyl sites, thus defining
two potentially independent or cooperative coordinating sites on
the same chiral scaffold (Fig. 3, right).
Finally, enantiopure samples of esters 6 and 9 were subjected to
racemization by heating in heptanes at 373 K and in N-methyl-2-
pyrrolidone at 453 K with monitoring the course of racemization
by analytical chiral HPLC (Fig. 5). Inversion barriers for 6 and 9 in
heptanes were determined as 125.3 kJ/mol and 130.9 kJ/mol
(30.0 kcal/mol and 31.3 kcal/mol), respectively, with similar values
(134.2 kJ/mol and 134.3 kJ/mol) obtained in NMP.16 These values are
consistent with the findings that the 10-membered ring system
does not undergo inversion and is effectively locked in the chair
conformation.17
These racemization rates confirm that [2.2]metacyclophane in-
version barriers are not overly affected by substituents on the aryl
rings as they lie in a similar range to other reported values of chiral
[2.2]metacyclophanes.5b In addition, these values compare favor-
ably with [2.2]paracyclophanes, for example, the C4 carboxymethyl
derivative has an inversion barrier of 158.0 kJ/mol.18
Fig. 3. Views of X-ray structures of 6 (top) and 8 (bottom).

M. Blangetti et al. / Tetrahedron 69 (2013) 4285e4291
4289
100
90
80
70
60
50
40
30
20
10
0
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 912904 and 912905. Copies of the data
can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223 336033
or e-mail: deposit@ccdc.cam.ac.uk).
4.2. 2,20-(Ethane-1,2-diyl)bis(4-methylbenzoic acid) 320
%
A solution of 2,4-dimethylbenzoic acid (1) (451 mg, 3.00 mmol)
in THF (15 mL) under N2 at ꢀ78 ꢁC was treated dropwise over 5 min
with BuLi (2.40 M, 2.63 mL, 6.30 mmol) and stirred for 5 min. KOt-
Bu (1.0 M in THF, 3.30 mL, 3.30 mmol) was added dropwise over
5
min followed by 2,2,6,6-tetramethylpiperidine (0.56 mL,
3.30 mmol). The reaction mixture was stirred for 15 min at ꢀ78 ꢁC
and 1,2-dibromoethane (0.77 mL, 9.00 mmol) added and stirred for
a further 5 min. The reaction mixture was warmed to room tem-
perature under N2 and the solvent removed under reduced pres-
sure. The residue was dissolved in ethyl acetate (30 mL), washed
with HCl (2 M, 3ꢂ10 mL), dried over sodium sulfate, and concen-
trated to dryness. Trituration from diethyl ether with cooling gave
(3) as a colorless solid (367 mg, 82%), mp 287e288 ꢁC (lit.20 mp
289 ꢁC).
0
10
20
30
40
50
60
70
80
90
100
110
time (h)
Fig. 5. Racemization plots of 6 (blue) and 9 (green) in heptanes at 373 K.
3. Conclusion
1H NMR (500 MHz, DMSO-d6):
d 12.65 (br s, 2H), 7.74
(d, J¼8.4 Hz, 2H), 7.17e7.03 (m, 4H), 3.13 (s, 4H), 2.32 (s, 6H). 13C
In summary, a two-step synthesis of the planar chiral [2.2]
metacyclophane framework containing one or two carboxy func-
tional groups at the key C4/14 positions utilizing LiNK metalation
and oxidative CeC bond formation has been described. The planar
chiral derivatives have been characterized by X-ray crystallography
and NMR spectroscopy, and the racemic mixtures separated by
chiral HPLC. The ease of enantiomer separation and the relatively
high barrier to racemization indicates their potential as planar
chiral catalysts and ligands, which, to date, has not been explored.
The asymmetric synthesis of planar chiral [2.2]metacyclophanes is
currently under investigation and will be reported on in due course.
NMR (125 MHz, DMSO-d6):
d 169.0, 143.7, 142.1, 131.7, 131.0, 127.7,
127.1, 36.1, 21.4. HRMS-ESI [MꢀH]ꢀ: 297.1115, C18H17O4 requires
297.1127.
4.3. 2,20-(Ethane-1,2-diyl)bis(4-(deuteriomethyl)benzoic acid)
3-D2
A solution of 2,20-(ethane-1,2-diyl)bis(4-methylbenzoic acid)
(3) (60 mg, 0.20 mmol) in THF (10 mL) under N2 at ꢀ78 ꢁC was
treated dropwise over 5 min with BuLi (2.50 M, 0.33 mL,
0.82 mmol) and stirred for 5 min. KOt-Bu (1.0 M in THF, 0.42 mL,
0.42 mmol) was added dropwise over 5 min followed by 2,2,6,6-
4. Experimental
tetramethylpiperidine (71 mL, 0.42 mmol). The reaction mixture
4.1. General methods
was stirred for 15 min at ꢀ78 ꢁC and CD3OD (33
mL) added. The
reaction mixture was warmed under N2 to room temperature
and the solvent removed under reduced pressure. The residue
was dissolved in ethyl acetate (20 mL), washed with HCl (2 M,
3ꢂ10 mL), dried over sodium sulfate, and concentrated to dry-
ness to give (3-D2) as a colorless solid (51 mg, 84%, 80% D
incorporation).
All reactions involving air-sensitive reagents were performed
under nitrogen in oven-dried glassware using the syringe-septum
cap technique. All solvents were purified and degassed before
use. Chromatographic separations were carried out under pressure
on Merck silica gel 60 using flash-column techniques. Reactions
were monitored by thin-layer chromatography (TLC) carried out on
0.25 mm silica gel coated aluminum plates (60 Merck F254) with UV
light (254 nm) as the visualizing agent. Unless specified, all re-
agents were used as received without further purifications. TMP(H)
was distilled from CaH2 prior to use and THF was obtained from
a solvent purification system. BuLi was purchased as a 2.5 M so-
lution in hexanes. KOt-Bu was purchased as a 1 M solution in THF.
The exact concentration of the organolithium solution was de-
termined by titration with diphenylacetic acid in THF prior to use.19
1H NMR and 13C NMR spectra were recorded at room temperature
at 500 MHz and 100 or 125 MHz, respectively, and calibrated using
residual undeuterated solvent as an internal reference. 2H NMR
(92.07 MHz) spectra were obtained in DMSO-d6 using residual
DMSO as an internal standard. Compound 7 was synthesized as
previously reported.9 Optical rotations were measured at 589 nm.
Analytical chiral HPLC analyses were performed on Daicel Chir-
alpak and Daicel Chiralcel series columns (250 x 4.6 mm ID) using
heptane/ethanol as solvent mixtures. Semi-preparative HPLC
analyses were carried out on a Daicel Chiralcel OD column
(250ꢂ20 mm ID) using heptane/2-propanol as solvent mixtures.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
1H NMR (500 MHz, DMSO-d6):
(m, 4H), 3.17e3.06 (m, 4H), 2.30 (s, 2H), 2.28 (s, 2H). 13C NMR
d 7.81e7.69 (m, 2H), 7.17e7.06
(125 MHz, DMSO-d6):
d 169.0, 143.7, 142.1, 131.7, 131.0, 127.7, 127.1,
36.1, 21.4 (t, J¼19.5 Hz). 2H NMR (92.07 MHz, DMSO-d6):
d 2.29 (s).
HRMS-EI [M]þ: 300.1320, C18H16D2O4 requires 300.1331.
4.4. [2.2]Metacyclophane-4,14-dicarboxylic acid 511
A solution of 2,20-(ethane-1,2-diyl)bis(4-methylbenzoic acid) (3)
(241 mg, 0.81 mmol) in THF (25 mL) under N2 at ꢀ78 ꢁC
was treated dropwise over 5 min with BuLi (2.26 M, 1.47 mL,
3.32 mmol) and stirred for 5 min. KOt-Bu (1.0 M in THF, 1.70 mL,
1.70 mmol) was added dropwise over 5 min followed by 2,2,6,6-
tetramethylpiperidine (0.29 mL, 1.70 mmol). The reaction mixture
was stirred for 30 min during which time the temperature was raised
to ꢀ60 ꢁC. 1,2-Dibromoethane (0.16 mL, 2.43 mmol) was added, the
reaction mixture was warmed under N2 to room temperature, and
the solvent was removed under reduced pressure. The residue was
dissolved in diethyl ether (30 mL) and extracted with aqueous NaOH
(2 M, 20 mL). The basic aqueous solution was washed twice with
diethyl ether (30 mL), acidified to pH 1 with HCl (2 M, 40 mL), and
extracted with CH2Cl2 (3ꢂ30 mL). The organic phase was dried over

4290
M. Blangetti et al. / Tetrahedron 69 (2013) 4285e4291
sodium sulfate and concentrated to dryness. Purification, by passing,
the crude material through a short silica gel plug, eluting with 100:0
to 90:10 CH2Cl2/MeOH, gave (5) as a colorless solid (83 mg, 35%),
mp >350 ꢁC.
4.7. [2.2]Metacyclophane-4-carboxylic acid methyl ester 94a
A solution of [2,2]metacyclophane-4-carboxylic acid (8) (22 mg,
0.09 mmol) in methanol (10 mL) was treated with 12 M HCl (three
drops) and heated under reflux for 16 h. The solvent was removed
under reduced pressure and ethyl acetate (20 mL) was added. The
organic layer was washed with saturated NaHCO3 (10 mL) and
water (10 mL), dried over sodium sulfate, and concentrated to
dryness. Purification by silica gel chromatography, eluting with
90:10 cyclohexane/ethyl acetate, gave (9) as a colorless solid
(18 mg, 75%), mp 68e70 ꢁC (lit.4a mp 71e73 ꢁC).
1H NMR (500 MHz, CD3OD):
d
7.93 (d, J¼7.8 Hz, 2H), 7.16
(d, J¼7.8 Hz, 2H), 4.37e4.31 (m, 2H), 4.29e4.22 (m, 2H), 3.24e3.14
(m, 2H), 2.14e2.04 (m, 2H), 1.94e1.83 (m, 2H). 13C NMR (100 MHz,
CD3OD):
d 169.9, 142.5, 140.3, 137.3, 131.3, 125.0, 40.1, 37.8. IR
(KBr disc): 1679 cmꢀ1. HRMS-ESI [MꢀH]ꢀ: 295.0981, C18H15O4 re-
quires 295.0970.
1H NMR (500 MHz, CDCl3):
d
7.92 (d, J¼7.9 Hz, 1H), 7.31
4.5. [2.2]Metacyclophane-4,14-dicarboxylic acid dimethyl
ester 64c
(t, J¼7.5 Hz, 1H), 7.13e7.04 (m, 3H), 4.32 (s, 1H), 4.30 (s, 1H), 4.22
(dt, J¼11.9, 3.6 Hz, 1H), 3.92 (s, 3H), 3.19e3.10 (m, 3H), 2.24 (td,
J¼12.3, 3.2 Hz, 1H), 2.15e2.05 (m, 2H), 1.84 (td, J¼11.9, 3.3 Hz, 1H).
A solution of [2,2]metacyclophane-4,14-dicarboxylic acid (5)
(47 mg, 0.16 mmol) in methanol (20 mL) was treated with 12 M HCl
(three drops) and heated under reflux for 16 h. The solvent was
removed under reduced pressure and ethyl acetate (20 mL) was
added. The organic layer was washed with saturated NaHCO3
(10 mL) and water (10 mL), dried over sodium sulfate, and con-
centrated to dryness. Purification by silica gel chromatography,
eluting with 80:20 cyclohexane/diethyl ether, gave (6) as a colorless
solid (4.9 mg), mp 138e139 ꢁC (lit.4c mp 138e140 ꢁC).
13C NMR (125 MHz, CDCl3):
d 168.1, 143.3, 140.5, 139.3, 138.4, 138.1,
135.9, 131.1, 129.2, 126.2, 125.8, 125.4, 125.3, 51.8, 40.9, 40.7, 40.2,
39.0. IR (KBr disc): 1733 cmꢀ1. HRMS-EI [M]þ: 266.1299, C18H18O2
20
20
requires 266.1307. [
a]
þ5.5 (c 0.5, CHCl3) and [
a
]
ꢀ6.0 (c 0.5,
D
D
CHCl3) after chiral semi-preparative HPLC. Analytical chiral HPLC
analysis of the racemic mixture (254 nm UV detector, room tem-
perature, eluent: 0.2% ethanol in heptane, flow rate: 0.7 mL/min):
Daicel Chiralpak IA: t1¼13.0 min and t2¼15.5 min.
Daicel Chiralpak IB: t1¼9.4 min and t2¼11.4 min.
1H NMR (500 MHz, CDCl3):
d
7.94 (d, J¼7.9 Hz, 2H), 7.13 (d,
Daicel Chiralpak AS-H: t1¼8.7 min and t2¼9.3 min.
J¼7.9 Hz, 2H), 4.38e4.36 (m, 2H), 4.31e4.22 (m, 2H), 3.93 (s, 6H),
Daicel Chiralcel OJ-H: t1¼20.3 min and t2¼22.7 min.
3.23e3.14 (m, 2H), 2.14e2.06 (m, 2H), 2.01e1.92 (m, 2H). 13C NMR
(100 MHz, CDCl3): d 168.1,142.4,140.7,137.7,131.5,126.6,125.3, 51.9,
4.8. General procedure for the racemization of [2.2]meta-
cyclophanes (heptane)
40.6, 38.2. IR (KBr disc): 1736 cmꢀ1. HRMS-ESI [MþH]þ: 325.1456,
20
C20H21O4 requires 325.1440. [
a
]
D
þ77.5 (c 0.2, ethanol) and
20
[
a]
ꢀ76.7 (c 0.2, ethanol) after chiral semi-preparative HPLC.
D
In a round-bottom flask equipped with a reflux condenser,
a sample of enantiopure [2.2]metacyclophane (0.5 mg) was dis-
solved in heptane (1 mL) and the solution was heated at reflux
(373 K). At a specified time interval, a sample of 20 mL was taken
and directly submitted for HPLC analysis.
Analytical chiral HPLC analysis of the racemic mixture (254 nm UV
detector, room temperature, eluent: 2% ethanol in heptane, flow
rate: 1.0 mL/min):
Daicel Chiralpak IA: t1¼9.2 min and t2¼14.5 min.
Daicel Chiralpak IB: t1¼6.3 min and t2¼7.4 min.
Daicel Chiralpak AS-H: t1¼6.3 min and t2¼7.5 min.
Daicel Chiralcel OJ-H: t1¼14.0 min and t2¼19.6 min.
4.9. General procedure for the racemization of [2.2]meta-
cyclophanes (NMP)
4.6. [2.2]Metacyclophane-4-carboxylic acid 84a
In a round-bottom flask equipped with a reflux condenser,
a sample of enantiopure [2.2]metacyclophane (0.5 mg) was dis-
solved in N-methyl-2-pyrrolidone (1 mL) and the solution was
heated at 453 K. At a specified time interval, a sample (approx. vol.
A solution of 4-methyl-2-(3-methylphenethyl)benzoic acid (7)
(117 mg, 0.460 mmol) in THF (10 mL) under N2 at ꢀ78 ꢁC was
treated dropwise over
5 min with BuLi (2.50 M, 0.61 mL,
100 mL) was taken and rapidly cooled to room temperature with an
1.52 mmol) and stirred for 5 min. KOt-Bu (1.0 M in THF, 1.01 mL,
1.01 mmol) was added dropwise over min followed by
ice bath. Heptane (approx. vol. 0.5 mL) was added and, after a short
micro extraction, the upper heptane layer was isolated and sub-
mitted for HPLC analysis.
5
2,2,6,6-tetramethylpiperidine (0.17 mL, 1.01 mmol). The reaction
mixture was stirred for 30 min during which time the temperature
was raised to ꢀ60 ꢁC. 1,2-Dibromoethane (0.12 mL, 1.38 mmol)
was added and the mixture stirred for a further 5 min. The re-
action mixture was warmed under N2 to room temperature and
the solvent removed under reduced pressure. The residue was
dissolved in ethyl acetate (20 mL), washed with HCl (2 M,
3ꢂ10 mL), dried over sodium sulfate, and concentrated to dryness.
Purification by silica gel chromatography, eluting with 1:1 cyclo-
hexane/diethyl ether, gave (8) as a colorless solid (46 mg, 39%), mp
194e196 ꢁC (lit.4a mp 197e199 ꢁC).
Acknowledgements
We thank the European Research Association ERA-Chemistry
and the Irish Research Council (IRC) for financial support.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.03.076.
1H NMR (500 MHz, CD3OD):
d
7.83 (d, J¼7.9 Hz, 1H), 7.21
(t, J¼7.5 Hz, 1H), 7.06 (dd, J¼7.9, 1.4 Hz, 1H), 7.06e6.92 (m, 2H), 4.21
(s, 1H), 4.18 (s, 1H), 4.15 (dt, J¼11.9, 3.6 Hz, 1H), 3.09e3.04 (m, 2H),
3.01 (dt, J¼12.2, 3.6 Hz, 1H), 2.10 (td, J¼12.2, 3.1 Hz, 1H), 2.04e1.93
(m, 2H), 1.70 (td, J¼11.9, 3.1 Hz, 1H).
References and notes
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3. (a) David, O. R. P. Tetrahedron 2012, 68, 8977e8993; (b) Paradies, J. Synthesis
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