Synthesis, chiral resolution, and absolute configuration of dissymmetric 4,12-difunctionalized [2.2]paracyclophanes

Article abstract of DOI:10.1002/ejoc.201300412

Racemic 4,12-difunctionalized [2.2]paracyclophanes were synthesized and successfully resolved by (recycling) HPLC on a stationary CHIRALPAK IA phase at a semipreparative scale. Their absolute configurations were determined by X-ray crystal structure analy

Full text of DOI:10.1002/ejoc.201300412

FULL PAPER
DOI: 10.1002/ejoc.201300412
Synthesis, Chiral Resolution, and Absolute Configuration of Dissymmetric
4,12-Difunctionalized [2.2]Paracyclophanes
Georg Meyer-Eppler,[a] Elisabeth Vogelsang,[a] Christian Benkhäuser,[a] Andreas Schneider,[a]
Gregor Schnakenburg,[b] and Arne Lützen*[a]
Keywords: Cyclophanes / Chiral resolution / Liquid chromatography / Configuration determination / Chirality
Racemic 4,12-difunctionalized [2.2]paracyclophanes were
synthesized and successfully resolved by (recycling) HPLC
on a stationary CHIRALPAK IA phase at a semipreparative
scale. Their absolute configurations were determined by X-
ray crystal structure analysis and/or by comparison of their
specific optical rotations with literature data. These are valu-
able functionalized C2-symmetric building blocks for the for-
mation of more sophisticated V-shaped, chiral molecular
architectures, as demonstrated by some exploratory transfor-
mations.
Introduction
Ever since [2.2]paracyclophane was synthesized in 1949
by Brown and Farthing it has fascinated chemists around
the world due to the physical and chemical properties that
result from its unique structure.[1] Substitution of the [2.2]-
paracyclophane core often results in planar chiral com-
pounds and some of these have already found applications
in material science,[2] as supramolecular hydrogen-bond re-
ceptors,[3] or in stereoselective synthesis.[4] Pseudo-ortho
4,12- and pseudo-meta 4,15-substituted [2.2]paracyclo-
phanes are dissymmetric molecules when they carry two
identical substituents and some of these have also been suc-
cessfully applied as chiral ligands or organocatalysts. Pye
and Rossen, for instance, presented (RP)-4,12-bis(di-
Scheme 1. Versatile derivatives of [2.2]paracyclophane for catalysis.
folds bearing uncommon stereogenic elements such as a
chiral axis,[8] stereogenic nitrogen atoms,[9] or spirocom-
pounds[10] to be very advantageous for this purpose. Thus,
dissymmetric pseudo-ortho 4,12- and pseudo-meta 4,15-sub-
stituted [2.2]paracyclophanes attracted our interest as po-
tential building blocks for the preparation of new classes of
very rigid planar-chiral ligands for the formation of oligon-
uclear metal complexes and, hence, we started to explore
these compounds.
The main problem with this particular class of planar
chiral compounds, however, is to gain access to enantiomer-
ically pure products. In fact, there are only a rather limited
number of successfully resolved 4,12-disubstituted deriva-
tives available today.[4b,11] Pye and Rossen obtained enan-
tiomerically pure PHANEPHOS by resolution through
clathrate formation with a chiral auxiliary.[5] This could
then be used as a chiral ligand in Buchwald–Hartwig amin-
ation of racemic 4,12-dibromo[2.2]paracyclophane to
achieve a kinetic resolution, to some extent, since (SP)-
PHANEPHOS showed enantiomeric discrimination of
(RP)-4,12-dibromo[2.2]paracyclophane compared with its
optical antipode and, hence, allowed its isolation in enan-
tiomerically pure form.[12] In addition, there are also proto-
cols available for the resolution of 4,12-dihydroxy[2.2]para-
cyclophane[13] and [2.2]paracyclophane-4,12-dicarboxylic
acid.[14] Both of these are based on the formation of dia-
phenylphosphanyl)[2.2]paracyclophane
(PHANEPHOS;
Scheme 1) in 1997 and introduced the [2.2]paracyclophane
scaffold as the backbone for some powerful ligands that
could be used in various catalytic transformations.[5] In ad-
dition to PHANEPHOS, (Ϯ)-4,12-dihydroxy[2.2]paracyclo-
phane (PHANOL) has been demonstrated to be a versatile
organocatalyst.[6]
Our group is particularly interested in diastereoselective
self-assembly processes of metallosupramolecular aggre-
gates,[7] and we found dissymmetric, structurally rigid scaf-
[a] Kekulé-Institut für Organische Chemie und Biochemie,
Rheinische Friedrich-Wilhelms-Universität Bonn,
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Fax: +49-2228-73-9608
E-mail: arne.luetzen@uni-bonn.de
Homepage: www.chemie.uni-bonn.de/oc/forschung/
arbeitsgruppen/ak_lue
[b] Institut für anorganische Chemie, Rheinische Friedrich-
Wilhelms-Universität Bonn,
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300412.
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A. Lützen et al.
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stereomers with a chiral auxiliary. Very recently, Morisaki
and Chujo reported another versatile auxiliary-based ap-
proach whereby they converted the racemic 4,12-di-
bromo[2.2]paracyclophane into a separable mixture of dia-
stereomeric 4-bromo-12-p-toluene-sulfoxide[2.2]paracyclo-
phanes upon treatment with (1R,2S,5R)-menthyl (S)-p-tolu-
enesulfinate.[15] These optically pure sulfoxides could then
even be transformed into the corresponding 4,12-difor-
myl[2.2]paracyclophanes through nucleophilic substitution.
Finally, approaches that involve kinetic enzymatic resolu-
tion have also been developed.[16]
In this context, HPLC on chiral stationary phases, how-
ever, has only been reported as an analytical tool, and has
not yet been applied on a (semi)preparative scale.[13–16] In
most of the studies, CHIRALPAK AD and OD were em-
ployed as chiral stationary phases. In these systems the
polymeric chiral selector is not covalently attached to the
silica gel substrate but only physically adsorbed, which lim-
its the range of potential eluents to a great extent. On chiral
stationary phases of the next generation, the chiral selector
is immobilized, which allows a broader range of eluents and
also introduces new selectivity.
Scheme 2. Synthesis of 4,12-dibromo[2.2]paracyclophane [rac-3]
from [2.2]paracyclophane (1).
tivity in bromine-lithium exchange reactions, we were able
to insert hydroxy and formyl groups by adapting literature
procedures established by Hopf[19] and Rozenberg.[20]
In this work we present the synthesis of [2.2]paracyclo-
phane derivatives and a complementary resolution ap-
proach employing semipreparative HPLC on a stationary
phase with a covalently attached chiral selector that allowed
us to improve the resolution of planar-chiral [2.2]paracyclo-
phanes with regard to yield and optical purity.[17] In this
way we were not only able to resolve 4,12-dihydroxy[2.2]-
paracyclophane, 4,12-dibromo[2.2]paracyclophane, 4,12-
bis(diphenylphosphane oxide)[2.2]paracyclophane, and
[2.2]paracyclophane-4,12-dicarboxylic acid {indirectly after
saponification of chromatographically resolved di(4-
bromophenyl)[2.2]paracyclophane-4,12-dicarboxylate}, but
also extended the number of successfully resolved deriva-
tives by separating the enantiomers of 4,12-diiodo[2.2]para-
cyclophane, 4,12-diformyl[2.2]paracyclophane, and 4,12-
Scheme 3. Synthesis of functionalized racemic [2.2]paracyclo-
phanes 4–6 through bromine-lithium exchange.
Compound rac-4 was first synthesized by Cram in 1969
di(4-hydroxyphenyl)[2.2]paracyclophane. In the case of using a twofold bromine-lithium exchange followed by oxi-
4,12-dihalogenated [2.2]paracyclophanes, simple HPLC dation with PhNO2.[18] Braddock improved this approach
failed to resolve the isomers but recycling HPLC was suc- by using tetrahydrofuran (THF) instead of diethyl ether and
cessful. The absolute configuration of the isomers was de- thereby increased the yield from 16 to 35–45%.[16] Rozen-
termined by X-ray crystal structure analysis and/or, if avail- berg, however, performed a stepwise substitution through
able, by comparison of their optical rotation with literature monolithiation, followed by monoborylation with
data.
B(OMe)3 in diethyl ether, followed by oxidation and subse-
quent saponification of the borate upon treatment with
H2O2 and aqueous NaOH with the aim of resolving the
resulting racemic monohydroxy-monobromo compound
through diastereomeric ester formation. Subsequently, the
Results and Discussion
The starting material for the synthesis of all compounds second bromine atom was substituted by a hydroxyl group
was unsubstituted [2.2]paracyclophane (1; Scheme 2). Its by following the same protocol, giving rise to 4 in about
bromination is well-known and several methods have been 46% yield (calculated only for the two substitutions).[20]
described.[18,19]
When we ran this borylation/oxidation reaction in a
We used the method of Braddock to synthesize 4,16-di- concerted manner, i.e., a twofold substitution, we were able
bromo[2.2]paracyclophane (2).[16] Heating this compound to dramatically increase the yield of rac-4 to 80%
in triglyme, following the approach of Rossen and Pye, then (Scheme 3) .
led to rac-4,12-dibromo[2.2]paracyclophane (3).[12]
Upon addition of N-formylpiperidine to dilithiated 3 and
Compound rac-3 was then used as the starting material subsequent treatment with HCl, Hopf obtained rac-4,12-
for all further reactions (Scheme 3). Thanks to its high reac- diformyl[2.2]paracyclophane (5) in yields of 60–81%
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Dissymmetric 4,12-Difunctionalized [2.2]Paracyclophanes
(Scheme 3).[19] When we used N,N-dimethylformamide
(DMF) instead of N-formylpiperidine followed by quench-
ing with aqueous HCl, we obtained rac-5 in a yield of 83%.
To broaden our approach, we also prepared dicarboxylic
acid rac-6 and rac-di(phosphane oxide) rac-7 according to
literature protocols. Hence, rac-6 could be most conve-
niently synthesized by the addition of dry ice to a solution
of dilithiated 3,[21] and we obtained yields of between 60
and 90% for this transformation. Compound rac-7 was ob-
tained in 68% yield from the dilithiated [2.2]paracyclo-
phane after transmetallation and reaction with diphenyl-
phosphinic chloride.[5]
As mentioned above, resolution of the enantiomers of 4,
6, and 7 has been described in the literature. Whereas the
separation of rac-7 could be achieved through clathrate for-
mation with dibenzoyl-l-tartraic acid as a chiral auxiliary
in a quite elegant manner[5] that only requires a simple alk-
alization as an additional synthetic step, the enantiosepara-
tions of rac-4 and rac-6 proved to be more tedious. For
instance, the very long reaction time of 14 days required for
Braddock’s kinetic resolution of the previously synthesized
acetate of 4 by transformation with a commercially avail-
able lipase of Candida rugosa is not attractive.[16] Thus,
Jiang and Zhao developed an auxiliary-based approach
whereby (Ϯ)-4 was treated with (1S)-camphanoyl chloride
and the resulting diastereoisomers were separated by using
column chromatography.[13] In a similar approach, Jiang et
al. were also able to achieve the resolution of (Ϯ)-6 by treat-
ment of the corresponding diacid chloride with (1S)-hy-
droxymethyl-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptanes-3-
one to prepare complementary diastereomeric esters that
were amenable for separation by column chromatog-
raphy.[14] However, both approaches require two or three
additional synthetic steps to obtain the material in optically
pure form.
Figure 1. Chromatographic resolution of rac-4 by analytical HPLC
on an analytical chiral CHIRALPAK IA phase (n-hexane/ethanol,
75:25 v/v; flow rate 1.0 mLmin–1).
configuration of the resolved material through X-ray crys-
tallography by analysis of the Flack parameter if suitable
single-crystals could be grown and also to further elaborate
this molecular architecture in nucleophilic substitutions.
Fortunately, at least the first two points turned out to be
true because we were not only able to prepare the respective
di(4-bromophenyl) ester rac-8 in excellent yield (Scheme 4)
but could also readily resolve the enantiomers on the chiral
stationary phase using n-hexane/ethanol (90:10 v/v) as elu-
ent.
With our experience in HPLC-based resolutions,[9e,9i] we
wanted to employ this technique for the direct separation
of racemic 4, 5, and 7. In fact, all these compounds could
be resolved in a very efficient manner, both on an analytical Scheme 4. Synthesis of di(4-bromophenyl) ester 8.
and on a semipreparative scale, by using a chiral CHI-
RALPAK IA stationary phase and mixtures of n-hexane
Unfortunately, we did not succeed in growing suitable
and simple alcohols such as ethanol or 2-propanol as elu- crystals of the resolved diester, which would have allowed
ent, as illustrated for 4 in Figure 1.
its absolute stereochemistry to be determined directly. Sim-
Comparison of the specific optical rotations of the re- ple saponification of the diester under alkaline conditions,
solved material with literature data[13–15] then allowed the however, provided the enantiomerically pure diacid, the
configuration of (–)-(Sp)-4, (+)-(Rp)-4, (+)-(Sp)-5, (–)-(Rp)- specific optical rotation of which could be compared with
5, (–)-(Rp)-7, and (+)-(Sp)-7 to be assigned.
the literature data. Thus, the (–)-enantiomer of 6 could be
Unfortunately, the high polarity of (Ϯ)-6 rendered it un- assigned the (Rp)-configuration and the (+)-enantiomer the
suitable for HPLC on this stationary phase. Therefore, we (Sp)-configuration. Since chiral [2.2]paracyclophanes are
thought to transform this compound into the correspond- configurationally very stable because they do not contain
ing diester via its diacid chloride first. As the alcohol com- α-hydrogen atoms and only begin to racemize at high tem-
ponent, we selected 4-bromophenol for several reasons: peratures of at least 150 °C or higher, depending on the
firstly, a phenol should be a good nucleophile with which substituents, it is safe to assign the same configuration to
to achieve diester formation in very good yield; secondly, the corresponding esters, i.e., (–)-(Sp)-8 and (+)-(Rp)-8
this diester should be easy to separate by HPLC due to its (please note that the sense of rotation changes).
rigid structure with its moderately polar functional groups
Although the sense of rotation of the enantiomers of our
pointing in defined directions, and, thirdly, the bromine dialdehyde 5 nicely corresponds to the literature data,[15] we
atoms provide a means with which to assign the absolute wanted to establish an additional independent proof for the
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A. Lützen et al.
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assignment. The absolute configuration of an organic mole- ditional experimental proof for the extraordinary high con-
cule can either be elucidated by analysis of the Flack pa- figurational stability of chiral [2.2]paracyclophanes because
rameter determined through X-ray diffraction of a single the precursor diol (Rp)-4 had the same configuration.
crystal, or by analysis of its CD spectrum. To apply the X-
Unfortunately, Suzuki reactions of 10 mostly produced
ray diffraction technique, however, it is mandatory that the mainly monoarylated products,[27] which might, however, be
compound contains a heavy atom. Although dialdehyde 5 very useful for the synthesis of asymmetric derivatives.
does not contain such atoms, fortunately, the first eluting Thus, we decided to prepare the previously unknown 4,12-
enantiomer (+)-5 could be easily transformed into its corre- diiodo[2.2]paracyclophane (12) by quenching dilithiated 3
sponding (4-bromophenyl)hydrazone 9 (Scheme 5), which with iodide (Scheme 7).
readily crystallized and whose molecular structure could be
determined by X-ray diffraction analysis (see Figure 3 be-
low) and revealed the (Sp)-configuration of (+)-5.
Scheme 7. Synthesis of rac-4,12-diiodo[2.2]paracyclophane [rac-
12].
To our delight, 12 showed very high reactivity in Suzuki
Scheme 5. Synthesis of (Sp)-(4-bromophenyl)hydrazone 9 from
cross-coupling reactions and led to the desired symmetri-
enantiopure (+)-(Sp)-5.
cally disubstituted dissymmetric target compounds; an ex-
ample is depicted in Scheme 8. The reaction of rac-12 with
4-methoxyphenyl boronic acid gave the desired diarylated
product rac-13 in almost quantitative yield, which could be
readily deprotected to give diol rac-14 upon treatment with
BBr3.
All the resolved compounds can be envisioned to act as
versatile starting materials for the synthesis of more sophis-
ticated molecular architectures, and we decided to explore
this further with some of the optically pure compounds de-
veloped here. Compound 4, for example, could be trans-
formed into the corresponding ditriflate 10 (Scheme 6). De-
spite the fact that racemic dibromide 3 has already been
shown to be reactive in Heck[22] and Suzuki[23] type aryl-
ations and Buchwald–Hartwig aminations,[12,24] unfortu-
nately, it proved to be almost completely unreactive in
Sonogashira like transformations in our hands.[25] Follow-
ing an approach developed by Hopf,[19] however, an alter-
native route to 4,12-diethinyl[2.2]paracyclophane (11) was
to treat 5 with the Bestmann–Ohira reagent[26] (Scheme 6).
Scheme 8. Synthesis of rac-13, rac-14, and enantiomerically pure
ditriflate 15 (from resolved 14).
Racemic diol 14 could then be resolved by HPLC using
the chiral CHIRALPAK IA stationary phase and a mixture
of n-hexane and 2-propanol (90:10 v/v) as eluent. The op-
tically pure compound could then be transformed into the
Scheme 6. Synthesis of enantiomerically pure ditriflate 10 and di-
ethynyl-substituted [2.2]paracyclophane 11.
The enantiomerically pure ditriflate (+)-10 could also be corresponding ditriflate 15 upon reaction with triflic anhy-
crystallized and analyzed by X-ray diffraction to reveal its dride. Again, 15 represents a valuable building block for the
(Rp)-configuration (see Figure 3 below). This provides ad- synthesis of larger V-shaped architectures and also contains
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Dissymmetric 4,12-Difunctionalized [2.2]Paracyclophanes
heavy atoms that can help to assign the absolute configura-
tion by X-ray crystallographic analysis (see Figure 3 below).
Although, we were able to resolve five different 4,12-di-
functionalized [2.2]paracyclophanes by using our approach,
it would be preferable to resolve the two dihalogenated
compounds 3 and 12 directly. In fact, Pye and Rossen were
able to resolve rac-3 by kinetic resolution in a Buchwald–
Hartwig amination by using enantiomerically pure
PHANEPHOS (7).[12] However, this approach provides ac-
cess to only one enantiomer of 3, with the second enantio-
mer being transformed irreversibly into a monoaminated
paracyclophane (although this is itself useful for the prepa-
ration of asymmetric derivatives). Thus, we considered
whether our HPLC approach could allow both enantiomers
to be obtained in a single separation. Unfortunately, all
attempts to separate the enantiomers of these compounds
in a single chromatographic run failed, because the differ-
ences in retention on the chiral phase were not sufficient to
achieve efficient resolution.
The problem of low chromatographic resolution de-
scribed above was finally solved by employing recycling
HPLC techniques. Although the concept of recycling
chromatography has been known for more than 50 years,[28]
and has developed into a standard tool in gel permeation
chromatography for polymer analytics,[29] it has so far re-
ceived much less attention for preparative enantiomer reso-
lution.[9i,30] With this technique we were able to resolve rac-
3 and rac-12 on a CHIRALPAK IA stationary phase and
mixtures of n-hexane and dichloromethane as eluent after
three cycles on an analytical scale (Figure 2) and after four
and five cycles on a semipreparative scale, respectively.
Figure 3. Molecular structures of (–)-(Rp)-3, (Sp)-9, (+)-(Rp)-10,
(+)-(Sp)-12, and (+)-(Sp)-15 as determined by X-ray diffraction
analyses; carbon (grey), hydrogen (light-gray), nitrogen (blue), oxy-
gen (red), sulfur (yellow), fluorine (green), bromine (brown), and
iodine (purple).
Conclusions
We have synthesized thirteen planar chiral dissymmetric
4,12-difunctionalized [2.2]paracyclophanes. Some have pre-
viously been prepared in racemic form (3–7, and 11) but
some have not been synthesized before (8–10 and 12–15). It
was possible to resolve seven of these racemic compounds
(3–5, 7, 8, 12, and 14) by (recycling) HPLC techniques on
an analytical and a semipreparative scale using a CHI-
RALPAK IA stationary phase. The absolute configurations
of the separated enantiomers were determined by anoma-
lous X-ray diffraction and/or confirmed by comparison of
their specific optical rotation with literature data. All of
these compounds represent interesting, configurationally
very stable building blocks for the synthesis of more sophis-
ticated molecular architectures based on the chiral V-
shaped structure of the [2.2]paracyclophane scaffold in en-
antiomerically pure form, as demonstrated by esterification,
ethynylation, arylation, and imine or hydrazone formation.
Figure 2. Chromatographic resolution of rac-12 by analytical
HPLC on an analytical chiral CHIRALPAK IA phase (n-hexane/
dichloromethane, 90:10 v/v; flow rate 1.5 mLmin–1).
Experimental Section
General: Reactions under inert gas atmosphere were performed un-
der argon using standard Schlenk techniques and oven-dried glass-
ware prior to use. Thin-layer chromatography were performed on
aluminum TLC plates (silica gel 60F254 from Merck). Detection
was carried out under UV light (254 and 366 nm). Products were
purified by column chromatography on silica gel 60 (70–230 mesh)
Enantiomerically pure dihalides 3 and 12 both crys-
tallized readily and, hence, their molecular structures and
absolute configurations could be determined and confirmed
by X-ray diffraction (Figure 3).
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A. Lützen et al.
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from Merck. 1H and 13C NMR spectra were recorded with a
Bruker DRX 500 spectrometer (300 K) operating at 500.1 and
125.8 MHz, a Bruker AM 400 (298 K) operating at 400.1 MHz and
100.6 MHz, or with a Bruker Avance 300 (298 K) operating at
300.1 MHz and 75.5 MHz, respectively. 1H NMR chemical shifts
are reported on the δ scale (ppm) relative to residual non-deuter-
ated solvent as the internal standard. 13C NMR chemical shifts are
reported on the δ scale (ppm) relative to deuterated solvent as the
internal standard. Signals were assigned on the basis of 1H, 13C,
HMQC, and HMBC NMR experiments. Mass spectra were re-
corded with a Finnigan MAT 212 with data system MMS-ICIS
(EI) or with a Bruker micrOTOF-Q (ESI). Elemental analyses were
carried out with a HeraeusVario EL. The HPLC analysis was per-
formed using a Prominence console from Shimadzu (binary recycl-
ing system) consisting of three pumps (LC20-AT), degasser (DGU-
20 A)3, diode array detector (SPD-M20 A), and a fraction collector
(FRC-10 A) or a smartline series from KNAUER with one S-1000
pump, autosampler S-3945, photodiode array detector S-2800, chi-
ral detector of IBZ Meßtechnik or a smartline series from
KNAUER with two S-1000 pumps, assistant 6000 with feed pump
and UV-detector S-2500. Chiral analytical (4.6ϫ 250 mm) and se-
mipreparative (10ϫ 250 mm) stationary phases CHIRALPAK IA
from DAICEL were applied and solvent mixtures of n-heptane and
dichloromethane (HPLC quality) and n-hexane and ethanol or 2-
propanol (HPLC quality) were used.
nBuLi (2.5 m in hexane, 2.73 mL, 6.83 mmol) was slowly added by
using a syringe. The solution was stirred for 1 h at 0 °C, then DMF
(0.58 mL, 7.5 mmol) was added. The solution was warmed to room
temperature and stirred for 1 h, then aq. HCl (4 m, 5.6 mL,
22.5 mmol) was added and the mixture was stirred for 2 h. The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (2ϫ 25 mL). The combined organic layers were washed
with dilute aq. HCl, saturated NaHCO3, and brine, and dried with
Mg2SO4. The solvent was evaporated and the crude product was
purified by column chromatography on silica gel [cyclohexane/ethyl
acetate, 5:1 (v/v); Rf = 0.5], yield 0.600 g (2.27 mmol, 83%). The
analytical data were in accordance with the literature data.[19]
Separation of Enantiomers: HPLC [chiral phase (semipreparative):
CHIRALPAK IA; n-hexane/EtOH (75:25); f = 5.0 mLmin–1; load-
ing: 20 mg of racemic material per run]: Rt = 13.3 {(+)-(Sp)-5;
[α]2D0 = +90.0 (c = 5.70 mgmL–1, THF), 99.7%ee}, 18.7 (–)-(Rp)-5;
[α]2D0 = –90.5 (c = 5.30 mgmL–1, THF), 99.9%ee} min.
(Rp)- and (Sp)-[2.2]Paracyclophane-4,12-dicarboxylic Acid [(Rp)- and
(Sp)-(6)]: KOtBu (0.337 g, 3.00 mmol) was dissolved in water
(0.54 mL, 3.00 mmol) and THF (40 mL), and enantiomerically
pure 8 (0.150 g, 0.25 mmol) was added. The resulting mixture was
stirred overnight, then the THF was evaporated and water was
added. The mixture was acidified with aq. HCl (2 m) and the white
precipitate was filtered off and washed with water and Et2O to give
the enantiomerically pure target compound, yield 0.068 g
(0.23 mmol, 92%).
Most solvents were dried, distilled, and stored under argon accord-
ing to standard procedures. All chemicals were used as received
from commercial sources. rac-4,16-Dibromo[2.2]paracyclophane
[rac-2],[16] rac-4,12-dibromo[2.2]paracyclophane [rac-3],[5] rac-[2.2]-
paracyclo-phane-4,12-dicarboxylic acid [rac-6],[21] and rac-4,12-
bis(diphenylphosphane oxide)[2.2]paracyclophane [rac-7][5] were
prepared according to literature protocols.
Compound (+)-(Sp)-6: [α]2D0 = +149.0 (c = 4.15 mgmL–1, EtOH).
Compound (–)-(Rp)-6: [α]2D0 = –150.0 (c = 4.00 mgmL–1, EtOH).
(Rp)- and (Sp)-4,12-Bis(diphenylphosphane Oxide)[2.2]paracyclo-
phane [(Rp)- and (Sp)-7]: Separation of enantiomers by HPLC [chi-
ral phase (semipreparative): CHIRALPAK IA; n-hexane/2-prop-
anol (90:10); f = 6.0 mLmin–1; loading: 10.5 mg of racemic material
per run]: Rt = 9.4 {(–)-(RP)-7; [α]2D0 = –105.0 (c = 2.00 mgmL–1,
ethanol), Ͼ99.9%ee}, 16.9 {(+)-(SP)-7; [α]2D0 = +106.0 (c =
2.00 mgmL–1, ethanol), Ͼ99.9%ee} min.
(Rp)- and (Sp)-4,12-Dibromo[2.2]paracyclophane [(Rp)-3 and (Sp)-3]:
Separation of enantiomers by HPLC [chiral phase (semiprepar-
ative): CHIRALPAK IA; n-heptane/CH2Cl2 (90:10);
f
=
3.0 Lmin–1; loading: 10 mg of racemic material per run]: Rt = 36.1
{(–)-(Rp)-3; [α]2D0 = –135.5 (c = 3.85 mgmL–1, THF), Ͼ99.9%ee},
39.2 {(+)-(Sp)-3; [α]2D0
= +133.4 (c =
3.75 mgmL–1, THF),
rac-Di(4-bromophenyl)[2.2]paracyclophane-4,12-dicarboxylate [rac-
8]: rac-6 (0.400 g, 1.35 mmol) was dissolved in anhydrous Et2O
(60 mL) and oxalyl chloride (0.24 mL, 2.97 mmol) and one drop of
DMF were added and the resulting mixture was stirred for 2 h
at room temperature. The solvent was evaporated and anhydrous
CH2Cl2 (10 mL) was added to the white residue. Triethylamine
(10 mL) was added (the solution became red), then 4-bromophenol
(0.584 g, 3.38 mmol) was added (the solution became yellow). The
solution was stirred at room temperature overnight and then
poured into ice water. The mixture was acidified and the layers
were separated. The aqueous layer was extracted with CH2Cl2 (3ϫ
10 mL), and the combined organic layers were washed with satu-
rated aq. NaHCO3 and brine and dried with Mg2SO4. The product
was obtained as a white powder. If required the product could be
further purified by column chromatography on silica gel [cyclohex-
ane/ethyl acetate, 2:1 (v/v); Rf = 0.8], yield 0.737 g (1.22 mmol,
90%). 1H NMR (400.1 MHz, CDCl3): δ = 2.88–2.96 (m, 2 H, 2-H,
10-H), 3.17–3.32 (m, 4 H, 1-H, 9-H), 4.15–4.21 (m, 2 H, 2-H, 10-
H), 6.68 (d, 3J8,7 = 3J16,15 = 8.3 Hz, 2 H, 8-H, 16-H), 6.85 (dd, 3J7,8
99.8%ee} min. Suitable crystals for X-ray-diffraction analysis were
grown from a mixture of dichloromethane and cyclohexane.
rac-4,12-Dihydroxy[2.2]paracyclophane [rac-4]: rac-3 (1.08 g,
2.80 mmol) was dissolved in anhydrous Et2O (80 mL) and cooled
to 0 °C, then nBuLi (2.5 m in hexane, 3.0 mL, 7.50 mmol) was
slowly added by using a syringe. The solution was stirred for 1 h
at 0 °C, then trimethyl borate (1.7 mL, 15.19 mmol) was added.
The solution was warmed to room temperature and stirred for an-
other 1 h, then aq. NaOH (0.5 m, 4.0 mL, 1.90 mmol) and H2O2
(35%, 3.0 mL, 30.38 mmol) were added and the solution was
stirred for 30 min. The layers were separated and the aqueous layer
was extracted with CH2Cl2 (2ϫ 25 mL). The combined organic
layers were washed with brine and dried with Mg2SO4. The sol-
vents were evaporated and crude 4 was purified by column
chromatography on silica gel (cyclohexane/ethyl acetate, 1:1 (v/v);
Rf = 0.6), yield 0.568 g (2.36 mmol, 80%). The analytical data were
in accordance with the literature data.[13]
Separation of Enantiomers: HPLC [chiral phase (semipreparative):
CHIRALPAK IA; n-hexane/EtOH (75:25); f = 4.8 mL min–1; load-
ing: 40 mg of racemic material per run]: Rt = 7.10 {(–)-(Sp)-4;
[α]2D0 = –117.0 (c = 3.44 mgmL–1, THF), Ͼ99.9%ee}, 13.6 {(+)-
(Rp)-4; [α]2D0 = +116.0 (c = 3.75 mgmL–1, THF), Ͼ99.9%ee} min.
3
4
4
= J15,16 = 8.3, J7,5 = J15,13 = 1.8 Hz, 2 H, 7-H, 15-H), 7.07 (d,
4
3J = 8.90 Hz, 4 H, H-phenyl), 7.43 (d, J5,7
=
4J13,15 = 1.8 Hz, 2
H, 5-H, 13-H), 7.50 (d, J = 8.90 Hz, 4 H, H-Ph) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 34.4 (C-1, C-9), 36.2 (C-2, C-10), 119.2
(C-21), 123.8 (C-19), 129.5 (C-4, C-12), 132.7 (C-20), 134.1 (C-5,
C-13), 136.6 (C-8, C-16), 137.4 (C-7, C-15), 140.8 (C-6, C-14),
143.7 (C-3, C-11), 150.0 (C-18), 165.0 (C-17) ppm. MS (EI): m/z
3
4,12-Diformyl[2.2]paracyclophane [rac-5]: rac-3 (1.00 g, 2.73 mmol)
was dissolved in anhydrous Et2O (80 mL) and cooled to 0 °C, then
4528
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4523–4532

Dissymmetric 4,12-Difunctionalized [2.2]Paracyclophanes
(%)
=
606.0
(15)
[C30H22Br2O4]+,
433.0
(80)
combined organic layers were washed with brine and dried with
MgSO4. The solvent was evaporated and the crude product was
purified by column chromatography on silica gel (ethyl acetate/cy-
clohexane, 5%; Rf = 0.8) to give the product as a light-yellow pow-
der, yield 0.410 g (1.61 mmol, 85%). 1H NMR (400.1 MHz,
CDCl3): δ = 2.79–2.86 (m, 2 H, 2-H, 10-H), 3.01–3.07 (m, 2 H, 1-
H, 9-H), 3.12–3.19 (m, 2 H, 1-H, 9-H), 3.29 (s, 2 H, 18-H, 20-H),
3.55–3.62 (m, 2 H, 2-H, 10-H), 6.50 (d, 3J8,7 = 3J16,15 = 7.6 Hz, 2 H,
[C24H18BrO3]+, 131.0 (100) [C9H7O]+. C30H22Br2O4 (606.30): calcd.
C 59.43, H 3.66; found C 59.35, H 4.01.
Separation of Enantiomers: HPLC [chiral phase (semipreparative):
CHIRALPAK IA; n-hexane/EtOH (90:10); f = 5.0 mLmin–1; load-
ing: 30 mg of racemic material per run]: Rt = 18.1 {(–)-(Sp)-8;
[α]2D0 = –59.0 (c = 5.30 mgmL–1, THF), Ͼ99.9%ee}, 27.4 {(+)-(Rp)-
8; [α]2D0 = +58.0 (c = 5.85 mgmL–1, THF), Ͼ99.9%ee} min.
8-H, 16-H), 6.55 (dd, 3J7,8 = 3J15,16 = 7.6, 4J7,5 = 4J15,13 = 1.7 Hz, 2
4
H, 7-H, 15-H), 7.07 (d, J5,7
=
4J13,15 = 1.7 Hz, 2 H, 5-H, 13-
(Sp)-4,12-Di[(4-bromophenyl)hydrazone][2.2]paracyclophane [(Sp)-9]:
4-Bromohydrazine (0.45 g) was dissolved in conc. H2SO4 (2 mL)
and water (3 mL), EtOH (10 mL) was added and the precipitate
was filtered off. Compound (Sp)-5 (0.100 g, 0.273 mmol) was dis-
solved in CH2Cl2 (2 mL) and added to the 4-bromohydrazine solu-
tion. After standing at room temperature overnight a precipitate
was formed that was filtered off and washed with water and EtOH.
The crude product was recrystallized from EtOH as brownish need-
les that were suitable for X-ray diffraction analysis. 1H NMR
(400.1 MHz, CDCl3): δ = 2.86–2.93 (m, 2 H, 2-H, 10-H), 2.97–3.04
(m, 2 H, H-, 9-H), 3.15–3.21 (m, 2 H, 1-H, 9-H), 3.78–3.83 (m, 2
H, 2-H, 10-H), 6.53 (m, 4 H, 8-H, 16-H, 7-H, 15-H), 6.89 (s, 2 H,
5-H, 13-H), 6.93 (d, J = 9.0 Hz, 2 H, H-Ph), 6.30 (d, J = 9.0 Hz,
2 H, H-Ph), 7.60 (s, 2 H, CHN) ppm. 13C NMR (100.6 MHz, [D6]-
DMSO): δ = 33.1 (C-2, C-10), 34.3 (C-1, C-9), 109.3 [C-Ph(Br)],
113.8 (C-Ph), 131.0 (C-6*, C-14*), 131.4 (C-4* C-12*), 131.9 (C-
Ph), 132.1 (C-3*, C-11*), 135.7 (C-8, C-16), 137.1 (C-5, C-13),
137.8 (C-7, C-15), 139.6 [C-Ph(NH)], 144.8 (C-CHN) ppm {*: as-
signment might be interchanged}. MS (ESI): m/z (%) = 601.06 (60)
[C30H26Br2N4 + H]+, 623.0 (100) [C30H26Br2N4 + Na]+.
H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 33.3 (C-1, C-9), 34.1
(C-2, C-10), 80.4 (C-18, C-20), 83.4 (C-17, C-19), 123.6 (C-4, C-
12), 133.5 (C-7*, C-15*), 133.5 (C-8*, C-16*), 134.4 (C-5, C-13),
139.6 (C-6, C-14), 142.7 (C-3, C-11) ppm {*: assignment might be
interchanged}. MS (EI): m/z (%) = 256.2 (96) [C20H16]+, 128.1 (100)
[C10H8]+. C20H16 (256.34)·0.5H2O: calcd. C 90.53, H 6.46; found
C 90.97, H 6.43. The analytical data are in accordance with the
reported data for the racemic compound.[19]
Compound (+)-(Sp)-11: [α]2D0 = +50.0 (c = 1.80 mgmL–1, THF).
Compound (–)-(Rp)-11: [α]2D0 = –49.0 (c = 2.14 mgmL–1, THF).
3
3
rac-4,12-Diiodo[2.2]paracyclophane
[rac-12]: rac-3
(0.800 g,
2.19 mmol) was dissolved in anhydrous Et2O (40 mL) and cooled
to 0 °C, then nBuLi (2.5m in hexanes, 2.19 mL, 5.46 mmol) was
slowly added by using a syringe and the solution was stirred for
1 h. Iodine (1.67 g, 6.57 mmol) was added, then the solution was
warmed to room temperature and stirred for 2 h. The reaction mix-
ture was diluted with CH2Cl2 and water and the layers separated.
The organic layer was washed with Na2SO3, water, and brine, and
dried with MgSO4. The solvent was evaporated and the crude prod-
uct was purified by column chromatography on silica gel (ethyl
acetate/cyclohexane, 5%; Rf = 0.7) to give the product as a light-
yellow powder, yield 0.867 g (1.88 mmol, 86%). Suitable crystals
for X-ray diffraction analysis were grown from a mixture of dichlo-
romethane and cyclohexane. 1H NMR (400.1 MHz, CDCl3): δ =
2.88–2.99 (m, 4 H, 1-H, 9-H), 3.01–3.13 (m, 2 H, 2-H, 10-H), 3.34–
(Rp)- and (Sp)-4,12-Di(trifluoromethylsulfonyl)[2.2]paracyclophane
[(Rp)- and (Sp)-10]: Enantiomerically pure 4 (0.21 g, 0.89 mmol)
was dissolved in anhydrous triethylamine (1.2 mL, 8.86 mmol) and
anhydrous CH2Cl2 (24 mL). The solution was cooled to –78 °C and
triflic anhydride (0.4 mL, 2.28 mmol) was added slowly by using a
syringe. The reaction mixture was warmed to room temperature,
then the solution was acidified with aq. HCl (2 m) and the layers
were separated. The aqueous layer was extracted with CH2Cl2
(20 mL) and the combined organic layers were washed with satu-
rated NaHCO3 and brine, and dried with MgSO4. The solvents
were evaporated and the crude product was purified by column
chromatography on silica gel [cyclohexane/ethyl acetate, 2:1 (v/v);
Rf = 0.6], yield 0.357 (0.71 mmol, 80%). Suitable crystals for X-ray
diffraction analysis were grown from a mixture of cyclohexane and
3
3
3.46 (m, 2 H, 2-H, 10-H), 6.49 (d, J8,7 = J12,13 = 7.6 Hz, 2 H, 8-
H, 16-H), 6.55 (dd, 3J7,8 = 3J13,12 = 7.6, 4J7,5 = 4J13,15 = 1.7 Hz, 2 H,
4
7-H, 15-H), 7.50 (d, J5,7 = 4J15,13 = 1.7 Hz, 2 H, 5-H, 13-H) ppm.
13CNMR (100.6 MHz, CDCl3): δ = 33.2 (C-1, C-9), 39.3 (C-2, C-
10), 103.8 (C-4, C-12), 132.5 (C-7, C-15), 133.8 (C-8, C-16), 138.6
(C-5, C-13), 140.5 (C-6, C-14), 142.5 (C-3, C-11) ppm. MS (EI):
m/z (%) = 360.0 (50) [C16H14I2]+, 230.0 (100) [C8H7I]+. C16H14I2
(460.09)·1/6hexane: calcd. C 43.13, H 3.26; found C 42.89, H 3.57.
1
ethyl acetate. H NMR (400.1 MHz, CDCl3): δ = 2.80–2.88 (m, 2
H, 1-H, 9-H), 3.10–3.14 (m, 4 H, 2-H, 10-H), 3.41–3.47 (m, 2 H,
Separation of Enantiomers: HPLC [chiral phase (semipreparative):
CHIRALPAK IA; n-hexane/EtOH (90:10); f = 3.0 mLmin–1; load-
ing: 10 mg of racemic material per run]: Rt = 38.48 {(–)-(Rp)-10;
[α]2D0 = –231.4 (c = 5.95 mgmL–1, THF), Ͼ99.9%ee}, 41.97 {(+)-
(Sp)-10; [α]2D0 = +229.8 (c = 7.10 mgmL–1, THF), 99.4%ee} min.
1-H, 9-H), 6.59–6.61 (m, 4 H, 5-H, 7-H, 13-H, 15-H), 6.67 (d, 3J8,7
3
= J16,15 = 7.7 Hz, 2 H, 8-H, 16-H) ppm. 13C NMR (100.6 MHz,
1
CDCl3): δ = 31.3 (C-2, C-10), 33.3 (C-1, C-9), 118.6 [CF3, JC,F
=
320 Hz], 124.3 (C-5, C-13), 132.0 (C-3, C-11), 133.1 (C-7, C-15),
136.4 (C-8, C-16), 143.2 (C-6, C-14), 148.3 (C-4, C-12) ppm. MS
(ESI): m/z (%) = 527.0 (100) [C18H14F6O6S2 + Na]+. C18H14F6O6S2
(504.42): calcd. C 42.69, H 2.91, S 12.67; found C 42.86, H 2.80, S
12.71.
rac-4,12-Di(4-methoxyphenyl)[2.2]paracyclophane
[rac-13]:
A
round-bottom flask with reflux condenser under inert gas was
charged with rac-12 (0.500 g, 1.075 mmol), 4-methoxyphenyl
boronic acid (0.370 g, 2.4 mmol), K3PO4 (3.370 g, 6.45 mmol),
Pd2(dba)3·CHCl3 (0.050 g, 0.05 mmol), and tricylcohexylphos-
phane (0.056 g, 0.20 mmol). 1,4-Dioxane (15 mL) and water
(1.5 mL) were added and the degassed suspension was heated to
reflux and stirred for 72 h. The reaction was quenched by addition
of saturated aq. EDTA and saturated aq. Na2CO3. The layers were
separated and the aqueous layer was extracted with CH2Cl2
(20 mL). The combined organic layers were dried with MgSO4 and
the solvents were evaporated. The crude product was purified by
Compound (–)-(Sp)-10: [α]2D0 = –20.0 (c = 4.33 mgmL–1, THF).
Compound (+)-(Rp)-10: [α]2D0 = +21.0 (c = 4.81 mgmL–1, THF).
(RP)- and (SP)-4,12-Diethynyl[2.2]paracyclophane [(RP)- and (SP)-
(11)]: Enantiomerically pure 5 (0.500 g, 1.89 mmol) and Cs2CO3
(2.407 g, 7.56 mmol) were suspended in anhydrous MeOH (40 mL)
and the Bestmann–Ohira reagent (1.390 g, 7.56 mmol) was added.
The resulting mixture was stirred for 24 h at room temperature,
then CH2Cl2 and water were added and the layers were separated. column chromatography on silica gel [cyclohexane/ethyl acetate, 4:1
The aqueous layer was extracted with CH2Cl2 (2ϫ 20 mL) and the (v/v); Rf
=
0.5], yield 0.443 (1.05 mmol, 98%). 1H NMR
Eur. J. Org. Chem. 2013, 4523–4532
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4529

A. Lützen et al.
(400.1 MHz, CDCl3): δ = 2.69–2.76 (m, 2 H, H-1, H-9), 2.89–2.97 H]+, 415.2 (100) [C28H24O2 + Na]+. C28H24O2 (392.49)·EtOH:
FULL PAPER
(m, 2 H, H-2, H-10), 3.06–3.12 (m, 2 H, H-1, H-9), 3.49–3.55 (m,
2 H, H-2, H-10), 3.87 (6 H, OMe), 6.60 (m, 4 H, H-7, H-15, H-5,
calcd. C 82.16, H 6.89; found C 82.72, H 6.85.
Separation of Enantiomers: HPLC [chiral phase (semipreparative):
CHIRALPAK IA; n-hexane/2-propanol (90:10); f = 8.0 mLmin–1;
loading: 30 mg of racemic material per run]: Rt = 13.0 {(–)-(Sp)-
14; [α]2D0 = –139.4 (c = 5.25 mgmL–1, THF), 99.5%ee}, 16.9 {(+)-
(Rp)-14; [α]2D0 = +142.0 (c = 5.70 mgmL–1, THF), 99.3%ee} min.
H-13), 6.70 (d, J8,7 = 4J16,15 = 8.2 Hz, 2 H, H-8, H-16), 6.94 (d J
= 8.7 Hz, 4 H, H-Ph), 7.28 (d, 3J = 8.7 Hz, 4 H, H-Ph) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 34.6 (C-1, C-9)*, 34.6 (C-2,
C-10)*, 55.5 (OMe), 113.9 (C-19), 130.0 (C-5, C-13), 130.3 (C-18),
131.8 (C-7, C-15), 133.9 (C-17), 135.6 (C-8, C-16), 136.9 (C-6, C-
14), 139.7 (C-3, C-11), 140.2 (C-4, C-12), 158.7 (C-20) ppm {*: as-
signment might be interchanged}. MS (EI): m/z (%) = 420.3 (50)
[C30H28O2]+, 211.1 (100) [C15H14O]+. C30H28O2 (420.54)·1͞3H2O:
calcd. C 84.47, H 6.77; found C 84.50, H 6.91.
4
3
(Rp)- and (Sp)-4,12-Di(4-trifluoromethylsulfonylphenyl)[2.2]para-
cyclophane [(Rp)- and (Sp)-15]: Enantiomerically pure 14 (0.110 g,
0.28 mmol) was dissolved in anhydrous CH2Cl2 (20 mL) and trieth-
ylamine (0.39 mL, 2.80 mmol) was added. The solution was cooled
to –78 °C and triflic anhydrate was added by using a syringe. After
complete addition, the solution was warmed to room temperature,
then aq. HCl (2 m) was added and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (20 mL) and the com-
bined organic layers were washed with saturated NaHCO3 and
brine, and dried with MgSO4. The solvent was evaporated to give
15 as a light-yellow powder, yield 0.155 g (0.24 mmol, 86%). Suit-
able crystals for X-ray diffraction analysis were grown from a mix-
rac-4,12-Di(4-hydroxyphenyl)[2.2]paracyclophane [rac-14]: rac-13
(0.200 g, 0.47 mmol) was dissolved in anhydrous CH2Cl2 (20 mL)
and cooled to –78 °C, then boron tribromide (1m in CH2Cl2,
2.82 mL, 2.82 mmol) was added and the solution was warmed to
room temperature. Water (100 mL) and CH2Cl2 (100 mL) were
added and the solution was neutralized with aq. NaOH (6 m). The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (20 mL). The combined organic layers were dried with
MgSO4 and the solvent was evaporated. The crude product was
purified by column chromatography on silica gel [cyclohexane/ethyl
acetate, 2:1 (v/v); Rf = 0.4], yield 0.184 (0.47 mmol, 99%). 1H NMR
1
ture of dichloromethane and cyclohexane. H NMR (400.1 MHz,
CDCl3): δ = 2.75–2.82 (m, 2 H, H-1, H-9), 2.99–3.06 (m, 2 H, H-
2, H-10), 3.13–3.20 (m, 2 H, H-1, H-9), 3.41–3.47 (m, 2 H, H-2,
4
4
(400.1 MHz, CDCl3): δ = 2.71–2.77 (m, 2 H, H-1, H-9), 2.89–2.97 H-10), 6.49 (d, J5,7 = J15,13 = 1.7 Hz, 2 H, H-5, H-13), 6.69 (dd,
3
4
4
(m, 2 H, H-2, H-10), 3.06–3.12 (m, 2 H, H-1, H-9), 3.47–3.54 (m,
3J7,8 = J13,12 = 7.7, J7,5 = J13,15 = 1.7 Hz, 2 H, H-7, H-15), 7.50
2 H, H-2, H-10), 5.42 (H, OH), 6.59 (m, 4 H, H-7, H-15, H-5, H- (d, 3J8,7 = 3J12,13 = 7.7 Hz, 2 H, H-8, H-16), 7.28–7.33 (m, 8 H, H-
4
4
3
13), 6.69 (d, J8,7 = J16,15 = 8.1 Hz, 2 H, H-8, H-16), 6.86 (d, J
= 8.7 Hz, 4 H, H-Ph), 7.21 (d, 3J = 8.7 Hz, 4 H, H-Ph) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 34.5 (C-1, C-9)*, 34.5 (C-2,
C-10)*, 115.4 (C-19), 130.0 (C-5, C-13), 130.5 (C-18), 131.9 (C-7,
Ph) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 34.0 (C-2, C-10),
34.6 (C-1, C-9), 118.8 (1JC,F = 321 Hz, CF3), 121.6 (C-19)*, 130.2
(C-5, C-13), 130.7 (C-18)*, 133.3 (C-7, C-15), 135.9 (C-8, C-16),
137.2 (C-3, C-11), 138.6 (C-4, C-12), 139.9 (C-6, C-14), 141.6 (C-
C-15), 134.0 (C-17), 135.6 (C-8, C-16), 136.9 (C-6, C-14), 139.7 (C- 17), 148.6 (C-20) ppm {*: assignment might be interchanged}. MS
3, C-11), 140.1 (C-4, C-12), 154.7 (C-20) ppm {*: assignment might (EI): m/z (%)
656.0 (60) [C30H28F6O6S2]+, 523.0 (55)
[C29H22F3O4S]+, 329.0 (40) [C15H14F3O3S]+, 179.1 (100) [C14H11]+.
=
be interchanged}. MS (ESI): m/z (%) = 393.2 (80) [C28H24O2
+
Table 1. Crystallographic data.
(–)-(RP)-3
(SP)-9
(+)-(RP)-10
(+)-(SP)-12
(+)-(RP)-15
Formula
Mr
T [K]
C16H14Br2
366.09
123(2)
C30H26Br2N4
602.37
123(2)
C18H14F6O6S2
504.41
123(2)
C16H14I2
460.07
123(2)
C30H22F6O6S2
656.60
123(2)
Crystal system
Space group
trigonal
P31
monoclinic
P21
monoclinic
P21
orthorhombic
P21212
orthorhombic
P212121
Crystal dimensions [mm]
a [Å]
b [Å]
c [Å]
0.32ϫ0.08ϫ0.06 0.71ϫ0.25ϫ0.04 0.13ϫ0.10ϫ0.02 0.42ϫ0.01ϫ0.08 0.30ϫ0.09ϫ0.05
12.202(6)
12.202(6)
7.810(4)
90
7.7215(5)
13.5762(13)
24.743(2)
90
9.5285(5)
9.2964(7)
12.6058(8)
90
9.2171(3)
9.2171(3)
17.1385(4)
90
11.6991(4)
17.3170(8)
42.001(2)
90
α [°]
β [°]
90
120
1007.0(18)
3
1.811
93.823(3)
90
2588.0(4)
4
1.546
3.159
111.984(4)
90
1035.41(12)
2
1.618
0.345
90
90
90
90
8509.2(6)
12
1.538
γ [°]
V [Å3]
1456.00(5)
4
2.099
Z
ρ [mg m3]
μ [mm–1]
6.016
4.300
0.272
θ range [°]
Completeness [%]
Reflections measured
Unique/observed
3.24–25.22
95.3
6695
2299/1308
(0.1577)
2299/19/163
0.917
1.71–28.00
99.6
20149
11266/7690
(0.0388)
11266/19/649
0.952
2.80–28.00
96.9
6775
4135/3703
(0.0398)
4135/1/289
1.080
2.21–27.98
99.5
175175
3482/3334
(0.0664)
3482/96/140
1.036
2.86–28.00
98.8
65319
19877/10607
(0.1584)
19877/104/1189
0.895
Reflections (Rint
)
Data/restrains/parameters
GoF on F2
Final R indices [IϾ2σ(I)]
R1 = 0.0803
ωR2 0.1270
R1 = 0.1296
ωR2 0.1390
R1 = 0.0419
ωR2 = 0.0727
R1 = 0.0834
ωR2 = 0.0855
–0.001(7)
R1 = 0.0518
ωR2 = 0.1346
R1 = 0.0582
ωR2 = 0.1378
0.07(12)
R1 = 0.0362
ωR2 = 0.0861
R1 = 0.0390
ωR2 = 0.0881
0.01(6)
R1 = 0.0670
ωR2 0.1333
R1 = 0.1291
ωR2 = 0.1544
0.02(8)
R indices all data
Absolute structure parameter X 0.03(3)
4530
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Eur. J. Org. Chem. 2013, 4523–4532

Dissymmetric 4,12-Difunctionalized [2.2]Paracyclophanes
C30H28F6O6S2 (565.61)·1͞3NEt3: calcd. C 55.67, H 3.94; found C
55.66, H 4.39.
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Compound (+)-(Rp)-15: [α]2D0 = +84.0 (c = 4.05 mgmL–1, THF).
Crystal Structure Determinations: X-ray crystallographic analyses
of (–)-(Rp)-3, (Sp)-9, (+)-(Rp)-10, and (+)-(Sp)-12: Data were col-
lected with a Nonius KappaCCD diffractometer equipped with a
low-temperature device (Cryostream, Oxford Cryosystems, 600er
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0.71071 Å). X-ray crystallographic analysis of (+)-(Rp)-15: Data set
was collected with an STOE IPDS2T with a low-temperature de-
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placed in calculated positions and refined isotropically using a ri-
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Diamond 3.0. For selected details of the crystallographic data see
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Acknowledgments
Financial support for this work from the Deutsche Forschungsge-
meinschaft (DFG) (SFB 624) and the Ministry of Innovation,
Science, and Research of the State of North Rhine-Westphalia
(ENQUETE) isgratefully acknowledged. G. S. thanks Prof. Dr. A. C.
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4531

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Received: March 19, 2013
Published Online: June 7, 2013
4532
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Eur. J. Org. Chem. 2013, 4523–4532