New [4.4]cyclophane diketals, monoketones, and diketones: Design, synthesis, and structural analysis

Article abstract of DOI:10.1002/ejoc.200700343

The synthesis of some new [4.4]cyclophane diketals, monoketones, and diketones in good yields is reported along with the unusually low reactivity towards hydrolysis of the spiro-1,3-dioxane rings connected to the cyclophane bridges. The structural analysis carried out by X-ray diffraction, NMR spectroscopy, and mass spectrometry shows significant intraand intermolecular π-π and C-H-π interactions. The rotation of the aromatic rings and the flipping of the bridges have been investigated by molecular modeling and variable-temperature NMR experiments. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700343

FULL PAPER
DOI: 10.1002/ejoc.200700343
New [4.4]Cyclophane Diketals, Monoketones, and Diketones:
Design, Synthesis, and Structural Analysis
Niculina Bogdan,[a,b] Ion Grosu,*[b] Eric Condamine,[c] Loïc Toupet,[d] Yvan Ramondenc,[c]
Ioan Silaghi-Dumitrescu,[b] Gérard Plé,[c] and Elena Bogdan[b]
Keywords: Cyclophanes / NMR spectroscopy / Pi interactions / X-ray diffraction / Molecular structures
The synthesis of some new [4.4]cyclophane diketals, mono-
ketones, and diketones in good yields is reported along with
the unusually low reactivity towards hydrolysis of the spiro-
1,3-dioxane rings connected to the cyclophane bridges. The
structural analysis carried out by X-ray diffraction, NMR
spectroscopy, and mass spectrometry shows significant intra-
and intermolecular π–π and C–H–π interactions. The rotation
of the aromatic rings and the flipping of the bridges have
been investigated by molecular modeling and variable-tem-
perature NMR experiments.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
tional processes determine the equilibria between homo-
meric structures[6a,6b] or between different stereoisomers
(syn and anti structures,[6c,6d] like and unlike isomers,[6e]
conformers with different arrangements of the aromatic
groups[6f–6h]). Some equilibria between cyclophanes with
edge-to-face and face-to-face disposed aromatic rings can
be controlled by electrochemical processes.[6i] The structural
aspects of the [4.4]cyclophane series have mainly been re-
vealed by NMR experiments[7] and single-crystal X-ray mo-
lecular structures.[5a,6a,6b]
Introduction
The properties of [4.4]cyclophanes[1] are somewhat be-
tween those of classic [2.2]cyclophanes and those of macro-
cycles with two (or more) aromatic rings which, formally,
are considered as cyclophanes too. The aromatic units of
[2.2]cyclophanes exhibit important interactions and the ro-
tation of the aromatic rings is totally constrained, while
macrocyclic cyclophanes show free or not completely hin-
dered rotation of the aromatic groups.[2] The interactions
between the aromatic parts in macrocyclic cyclophanes are
weak, but sometimes they are responsible for the shape of
the molecules in the solid state[3] and can determine the
preference of the compounds for peculiar conformers in
solution.[3a,4] Investigations of [4.4]cyclophanes have fo-
cused on the experimental and theoretical studies of the
interactions between the aromatic rings[5] and on the con-
formational processes involved in the flipping of the bridges
or the rotation of the aromatic units.[5,6] These conforma-
Recently,[8] we reported the synthesis of [7.7]cyclophanes
i and ii (Figure 1) starting from appropriate 1,3-dioxane de-
rivatives of 1,4-diacetylbenzene and 2,6-diacetylpyridine.
The substrates exhibit an axial orientation of the aromatic
groups with respect to both 1,3-dioxane rings and a favor-
able arrangement (preorganization) of the reacting groups
for high-yielding macrocyclization reactions. Encouraged
by the previous results, we considered it of interest to use
appropriate 1,3-dioxane derivatives of 1,4-diacetylbenzene
in order to synthesize new dispiro diketal [4.4]cyclophanes
iii (Figure 1) and the corresponding dioxocyclophanes and
to investigate their structures and conformational behavior.
The presence of 1,3-dioxane rings in iii is important, on
the one hand, because the conformational behavior of the
saturated heterocycles insures the required preorganization
of the substrate for the closure of the macrocycle and, on
the other hand, it facilitates the NMR investigation of the
rotation of the aromatic groups. The methylene groups of
the saturated heterocycles are differentiated (diastereotopic)
in the NMR spectra if the rotation of the nonsymmetric
aromatic ring (B) is hindered and they are rendered equiva-
lent if the rotation of aromatic ring (B) is fast enough (e.g.,
in the case of the dynamic NMR investigations of some 2-
aryl-2-methyl-1,3-dioxanes).[9]
[a] Marie Curie Excellence Team, Dept. Chemie, LS AC, Techni-
sche Universität München,
Lichtenbergstr. 4, 85747 Garching, Germany
Fax: +49-89-28-914-512
E-mail: niculina.bogdan@ch.tum.de
[b] Faculty of Chemistry and Chemical Engineering, “Babes-
Bolyai” University,
11 Arany Janos str., 400028, Cluj-Napoca, Romania,
Fax: +40-264-590-818
E-mail: igrosu@chem.ubbcluj.ro
[c] IRCOF, UMR 6014, Faculté des Sciences, Université de Rouen,
76821 Mont Saint-Aignan Cedex, France
[d] Université de Rennes I, UMR 6626,
35042 Rennes Cedex, France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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New [4.4]Cyclophane Diketals, Monoketones, and Diketones
by etherification reactions show in many cases lower val-
ues.[12] In order to access dioxocyclophanes, compounds 7–
9 were submitted to deprotection reactions of the ketal
groups (1,3-dioxane rings) using several methods. The usual
deprotections with I2 in acetone,[13] catalytic[14] or stoichio-
metric[15] amounts of cerium ammonium nitrate (CAN), or
6  HCl[16] failed for 8, but were successful in the cases of
7 and 9, leading to the monoketones 13 and 14 (Scheme 3).
All attempts to obtain (by the mentioned methods) the cor-
responding diketones starting from cyclophanes 7–9 or
from the monoprotected derivatives 13 and 14 (even under
harsh hydrolysis conditions: 6  HCl in MeCN, 64 h at re-
flux) failed, and monoketones 13 and 14 or decomposition
products were recovered. However, in the procedures with
6  HCl or with stoichiometric amounts of CAN, the for-
Figure 1. General formula of [7.7]cyclophanes i and ii and [4.4]-
cyclophanes iii with 1,3-dioxane units.
Results and Discussion
New [4.4]cyclophanes 6–9 and 11 were obtained
(Schemes 1 and 2) in good yields (34–67%) by the reaction
of several bis(bromomethyl)arenes 1–4 and 10 with diol 5
using a typical procedure for the synthesis of macrocyclic
ethers.[10] The 2,5-pyridinocyclophane 11 was transformed
with m-CPBA, in good yields (83%) into its N-oxide 12
(Scheme 2). The yields of the macrocyclization reactions are
remarkable. The synthesis of [4.4]cyclophanes with sulfur
atoms in the bridges (no diether [4.4]cyclophanes are re-
ported), despite the anion of the mercapto derivatives being
more reactive, has been achieved in similar or lower yields
(10–72%),[5a,11] and the reported yields for other macrocy-
clization reactions leading to the formation of cyclophanes
Scheme 2. Synthesis of 11 and 12.
Scheme 3. Synthesis of monoketones 13 and 14 and diketones 15
and 16.
Scheme 1. Synthesis of 6–9.
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I. Grosu et al.
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mation of small amounts of diketone 15 (Scheme 3) could bonyl carbon atoms was considered responsible for the low
be observed (NMR determined ratio of monoketone/dike- yields).[6c]
tone = 10:1). Surprisingly, the hydrolysis of 7 and 8 using a
mixture of CAN (10 mol-%) and 6  HCl (0.01 mL) was
successful, giving good yields of diketones 15 and 16 which
were isolated and characterized (Scheme 3). The dioxo[4.4]-
Structural Aspects in the Solid State
cyclophanes are important targets in host molecule chemis-
The molecular structures of cyclophanes 6, 7, 9, and 15
try due to their ability to act as exocyclic receptors (e.g., for (Figure 2) were obtained by single-crystal X-ray dif-
nucleic acids)[17] or they can be used as building blocks for fractometry. The 1,4-phenylene ring exhibits an axial orien-
further transformations. Despite the difficulties involved in tation with respect to both 1,3-dioxane rings (6, 7, and 9)
the deprotection step, we obtained dioxo[4.4]cyclophanes and its deformation (measured by the angle between the
15 and 16 in total yields of 41 and 61%, respectively. These bonds C5–C6 and C9–C10, Table 1) could be determined.
values are considerably higher than the yields (5–18%) re- The deformation angles decrease in the order ortho-phenyl-
ported for the direct macrocyclization method used to ob- ene Ͼ meta-phenylene Ͼ 1,4-naphthylene. The molecular
tain other dioxo[4.4]cyclophanes[6c,6d,6g] (the strain in the structures show almost parallel orientation of rings A and
target macrocycles due to the sp2 hybridization of the car- B in 9, face-tilted-to-face arrangement in 6, and edge-tilted-
Figure 2. ORTEP diagrams for compounds 6 (a), 7 (b), 9 (c), and 15 (d).
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New [4.4]Cyclophane Diketals, Monoketones, and Diketones
Table 1. Relevant structural data calculated from the molecular structures of 6, 7, 9, and 15.
[a]
[c]
[d]
[d]
Compd.
α1 [°]
d[b] [Å]
α2 [°]
α3 [°]
α4 [°]
6
7
23.6
57.4
17.3
42.9
H2–A 2.499
H20–A 3.078
H21–B 3.292, H22–B 3.316
H18–A 2.617
30.0
20.5
4.1
84.2
84.8
84.0
–
84.3
79.0 or 72.9
84.1
9
15
7.6
–
[a] α1 = angle between A and B. [b] Important distances for C–H–aromatic ring interactions, measured between the centers of the aromatic
rings. [c] Deformation of ring B: α2 = C5–C6/C9–C10. [d] Rotameric behavior of A: α3 = A/C4–C5–C6, α4 = A/C9–C10–C11; α3 and α4
exhibit values close to 0° for the bisectional rotamer of the 1,4-phenylene ring (A) and close to 90° for the orthogonal rotamer of this
group.
to-face arrangement in compounds 7 and 15 (Table 1, Fig- the dioxacyclohexane units and AB patterns for the protons
ure 2). The distances measured between some hydrogen of the same CH2 group in the bridges. Further freezing of
atoms and the neighboring aromatic rings (Table 1) reveal the flipping of the bridges determines (if the rotation of ring
C–H–π interactions (e.g., the distances between H20 in 7, B is already blocked) the recording of two sets of signals
H18 in 15, and H2 in 6 and the center of the aromatic ring (of different intensities) in the NMR spectra belonging to
A are 3.078, 2.617, and 2.499 Å, respectively). Investigation the syn and anti frozen diastereoisomers. Due to these par-
of the lattices of these compounds showed the assisted as- ticularities in the NMR spectra and to the fact that the
sembly of these molecules by C–H–π interactions (they are barrier for the flipping of the bridges is lower than the bar-
shown in the Supporting Information) which mainly involve rier for the rotation of the aromatic rings, the conforma-
the aromatic ring B and the hydrogen atoms belonging to tional equilibria of the [4.4]cyclophanes can be, step by step,
the CH2 groups of the bridges, the CH3 groups at positions monitored by dynamic NMR experiments. In order to ob-
5Ј and 5ЈЈ of the spiro-heterocycles, or the other aromatic serve the conformational behavior of [4.4]cyclophanes, we
ring A.
carried out variable-temperature NMR measurements with
compounds 6, 7, 9, 11, and 12.
Structural Aspects in Solution
The structural investigations in solution of the diketal
and monoketal [4.4]cyclophanes were carried out by per-
forming complex NMR experiments and were focused on
the conformational preferences of the dioxacyclohexane[18]
rings (C and D, Schemes 1 and 2), on the rotameric behav-
ior of the aromatic components (A and B) of the cy-
clophanes, and on the flipping equilibria of the bridges
(Scheme 4). The rotation of the aromatic rings A and B and
the flipping of the bridges (Scheme 4) can be monitored by
variable-temperature NMR experiments. These conforma-
tional equilibria involve homomeric structures if ring B is
symmetric or diastereoisomers if ring B is nonsymmetric. If
the part of the nonsymmetric B ring of highest precedence
(let us say that it is the one drawn in red in Scheme 4) is
close to the center of ring A, the diastereomer is denoted
as syn [enantiomeric structures v and vii in Scheme 4 (the
planar chiral configuration is inverted due to the rotation
of ring B)] and if this reference ring B is at a distance from
ring A, then the corresponding diastereoisomer is denoted
as anti (enantiomeric structures iv and vi, Scheme 4). The
rotation of ring B, as well as the flipping of the chains, leads
to an equilibration of the syn and anti structures. The syn
and anti diastereoisomers can be observed by NMR only if
both conformational equilibria are frozen. Rotation of ring
B (which changes the planar chiral configuration) renders
equivalent the CH2 groups of the 1,3-dioxane rings and the
Scheme 4. Rotation of the nonsymmetric aromatic ring B and flip-
ping of the bridges in [4.4]cyclophanes.
The room-temperature NMR investigations (1H, 13C,
protons of the same CH2 group of the chains. The freezing COSY, HMQC, HMBC, NOESY, and/or ROESY) reveal
of the rotation of ring B leads as a consequence to more different signals for the axial and equatorial protons of the
complicated NMR spectra with different signals for the saturated heterocycles, while the NOESY or ROESY spec-
protons at the diastereotopic positions 2Ј(2ЈЈ) and 4Ј(4ЈЈ) of tra show interactions between the signals of the aromatic
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Table 2. NMR spectroscopic data (CDCl3, 300 MHz) for 6–9 and 11–16.
δ [ppm]
Hax
Heq
4-CHH
11-CHH
2-CHH
13-CHH
2Ј(2ЈЈ), 4Ј(4ЈЈ)
2Ј(2ЈЈ), 4Ј(4ЈЈ)
6
7
3.51
3.47
3.31
3.72
3.63
3.37
3.46
3.57
3.78
3.53
4.30
4.27
8
9
3.09, 3.14
3.26, 3.32
3.52, 4.22
4.09, 5.44
11
12
13
14
15
16
3.33–3.43[a]
3.23–3.39[a]
4.02, 4.11
4.02, 4.49
5.53
3.49, 3.89
3.65, 3.87
3.56
4.27, 4.50
4.10, 5.25
4.34
4.10, 4.49
4.13, 4.28
4.11
3.49
3.16, 3.22
3.59
3.30, 3.37
4.70, 5.37
3.49, 4.10
4.57, 4.75
4.06, 5.33
–
–
–
–
4.54
4.40
4.14
4.49
[a] Overlapped peaks.
protons of ring A and the signals of the axial protons of one of the bridges can interact (C–H–π) with the aromatic
the 1,3-dioxane units. These NMR spectroscopic data dem- ring A (see the Supporting Information). The room-tem-
onstrate the anancomeric structure of the dioxacyclohexane perature NMR spectrum (Figure 4) shows that the four
rings in all the investigated derivatives and the axial-orthog- protons at positions 2 and 13 are rendered equivalent (as
onal orientation of the 1,4-phenylene ring (A) with respect well as those at positions 4 and 11) by the conformational
to both heterocycles in 6–9, 11, and 12 and with respect to equilibria of compound 6 (Scheme 5). These equilibria oc-
the remaining heterocycle in the monoketones 13 and 14 cur between four equivalent structures (viii–xi) and require
(Table 2). The preference for these conformations is also besides the flipping of the bridges (2), an inside–outside
predicted by molecular modeling (see the Supporting Infor- movement (1) of the α-CH2 groups (ring B is taken as a
mation). Despite the previously shown similarities between reference). In order to observe the specific conformational
the room-temperature NMR spectra of these compounds, equilibria, variable-temperature NMR experiments were
their analysis revealed significant differences and two carried out with 6 in CD2Cl2 (Figure 4) and in [D8]THF
groups of diketal and monoketal [4.4]cyclophanes could be
considered. The room-temperature NMR spectra of the
first considered group (compounds 6–8 and 13) do not dif-
ferentiate the protons at positions 2Ј(2ЈЈ) and 4Ј(4ЈЈ) of the
dioxacyclohexane rings or the protons of the same CH2
group of the bridges. These results, obtained at room tem-
perature, are supported by molecular modeling (calculated
barriers lower than 10 kcal/mol) and suggest the fast flip-
ping of the bridges in all these derivatives and the free rota-
tion of the nonsymmetric aromatic ring B in compounds 7
and 13.
Variable-temperature 1H NMR experiments were carried
out with 6 and 7. The spectra (CDCl3) of 7 run at lower
(up to 210 K) and higher (up to 320 K) temperatures were
not different to those recorded at room temperature. Molec-
ular modeling of this compound showed that the rotation
of ring B and the inversion of the chains are simultaneous.
The calculated barrier, as expected, is very low [5.16 kcal/
mol (PM3), 1.41 kcal/mol (B3LYP)]. The compound exhib-
its a preference for the syn structure (Figure 3) which corre-
sponds to the edge-tilted-to-face arrangement of the aro-
matic rings (calculated ∆Ganti–syn = 0.89 kcal/mol). The
preference for these structures is also supported by the
shielding of the signal belonging to the proton at position
20 (δ(20-H) = 6.28 ppm). The fast conformational equilib-
rium for 7 is also suggested by literature data[6c,6d] which
reveal low barriers for the flipping of the bridges in [4.4]-
metaparacyclophanes.
Molecular modeling predicts for 6 a stable structure, sim-
ilar to that observed in the solid state, which shows a tor-
sion of the bridges in which one of the hydrogen atoms of and the centroid of A are 3.114 and 3.679 Å, respectively].
Figure 3. syn and anti isomers of 7 [the distances between C(20)
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New [4.4]Cyclophane Diketals, Monoketones, and Diketones
(see the Supporting Information). The modifications to the mol) than for compound 7. This difference is probably due
spectra are similar in the two solvents. In Figure 4 it can be to the stabilization of the ground-state structures involved
observed that the coalescence of the signals belonging to in the flipping of the bridges of 6 by C–H–π interactions
the aromatic protons of ring A (δ298 = 7.39 ppm) occurs at between the α-CH2 groups and the 1,4-phenylene ring (A).
180 K. The coalescence of the signals of the protons of the This explanation is supported by the shielding of the signal
same CH2 group (δ298 = 3.47 and 3.68 ppm) of the bridges of these protons in 6 (CDCl3; δ2,13 = 3.53 ppm) as com-
begins at 220 K, and at 180 K the signals are completely pared with the signal of the corresponding protons in the
indistinguishable from the baseline. The modifications to 1H NMR spectrum of 7 (CDCl3; δ2,13 = 4.30 ppm).
the NMR spectra caused by decreasing the temperature
prove the flipping of the chains, but the conformational
equilibria for 6 could not be completely frozen until 180 K
in CD2Cl2 or 168 K in [D8]THF. In agreement with the re-
sults of the variable-temperature NMR experiments, molec-
ular modeling of 6 showed a higher value for the barrier
for the flipping of the bridges (∆G# = 9.79 kcal/mol; for the
inside–outside movement of the chains ∆G# = 4.71 kcal/
Scheme 5. Conformational equilibria for 6.
For the second group of compounds (9, 11, 12, and 14),
the room-temperature 1H NMR spectra exhibit different
signals for the CH2 groups [positions 2Ј(2ЈЈ) and 4Ј(4ЈЈ)] of
the same dioxacyclohexane ring and for the protons of the
same CH2 group of the chains. The more complex spectra
for these compounds reveal the hindrance of the rotation of
the nonsymmetric ring B at room temperature. The room-
temperature 1H NMR spectrum of 9 (Figure 5) exhibits two
doublets for the axial protons (δ = 3.11 and 3.16 ppm) and
two doublets of doublets for the equatorial protons (δ =
3.27 and 3.33 ppm; the further splitting of the signals is due
to the long-range coupling characteristics of the equatorial
protons of the 1,3-dioxane ring[19] of the dioxacyclohexane
rings and the signals pertaining to the protons of the dif-
ferent CH2 groups are AB systems (Table 2, Figure 5). The
structure of cyclophane 9 belongs to the Cs symmetry point
group and exhibits planar prochirality. Positions 2Ј(2ЈЈ) and
4Ј(4ЈЈ) (CH2 groups of the same dioxacyclohexane ring) are
diastereotopic, as well as the protons of the same CH2
group (either at positions 2 and 13 or at positions 4 and
11).[20] The two dioxacyclohexane rings (C and D), the two
benzyl-type CH2 groups (2 and 13), and the CH2 groups at
positions 4 and 11 are not different in the NMR spectrum.
1
An interesting feature in the H NMR spectrum of 9 is the
recording of different signals (δ = 6.06 and 7.03 ppm) for
the protons of the 1,4-phenylene ring. This fact proves the
hindrance of the rotation of the 1,4-phenylene ring, too.
Thus, in compound 9, the room-temperature rotation of
1
both aromatic rings A and B is blocked. In order to observe
the rotation of the rings, variable-temperature 1H NMR ex-
Figure 4. H NMR spectra (500 MHz) of compound 6 in CD2Cl2
at 298 (a), 220 (b), 200 (c), and 180 K (d).
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I. Grosu et al.
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periments (in [D6]DMSO) were carried out with 9 by rais-
ing the temperature to 390 K (a limit imposed by the appa-
ratus). The spectra at high temperatures did not show sig-
nificant modifications compared with the spectra run at
room temperature, but they proved the hindrance of the
rotation of the aromatic rings even at these temperatures.
We estimated (using Eyring’s equations)[21] the barrier for
the rotation of the aromatic rings in 9 to be higher than
20.1 kcal/mol.
Molecular modeling predicts for 11 and 12 more stable
syn structures (Figure 6; ∆G°anti–syn = 1.19 and 1.95 kcal/
mol, respectively) and lower barriers for the flipping of the
bridges [∆G#(11) = 15.12 and ∆G#(12) = 14.04 kcal/mol]
than for the rotation of the aromatic rings. The rotation of
ring B can occur in two ways: either with the nitrogen atom
or the CH group inside the cyclophane. For 12 only the
rotation with the CH group inside is thermodynamically
possible [∆G#(12) = 23.85 kcal/mol], while for 11 both
routes can be followed, but the calculated barrier for the
rotation with the nitrogen atom inside is lower [∆G#(11) =
15.08 and 22.31 kcal/mol for the rotation with the nitrogen
atom or the CH group inside, respectively].
The room-temperature NMR spectra of these com-
pounds show only one set of signals, with differentiation of
the CH2 groups of the same dioxacyclohexane ring and of
the protons of the same CH2 group of the bridges, and sug-
gest (at room temperature) the fast flipping of the chains
and hindrance of the rotation of the pyridine and pyridine
Figure 6. syn and anti isomers of 11 (the distances between the
oxide groups. The 1H NMR spectra of 11 and 12 (Figures 7, nitrogen atom and the centroid of A are 3.767 and 4.239 Å, respec-
tively).
8, and 9) are more complex than the spectrum of 9. Com-
pounds 11 and 12 belong to the C1 symmetry point group.
The plane of symmetry found in 9 does not exist in 11 and and 13), and the other two methylene groups (positions 4
12. As a consequence, the two dioxacyclohexane rings (C and 11) are different in the NMR spectra. At the same time,
and D), the two benzyl-type methylene groups (positions 2 if the rotation of the pyridine ring is frozen, the planar chi-
1
Figure 5. H NMR spectrum (room temp., CDCl3, 300 MHz, fragment) of 9.
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New [4.4]Cyclophane Diketals, Monoketones, and Diketones
rality of 11 and 12 determines the diastereotopicity of the (the spectra do not exhibit separated signals for the syn and
similar groups of the same dioxacyclohexane ring (ring C: anti structures). In order to obtain more details about the
positions 2Ј and 4Ј; ring D: positions 2ЈЈ and 4ЈЈ) and of conformational behavior of 11, variable-temperature NMR
the protons of the same CH2 group. The room-temperature experiments were carried out, either by increasing the tem-
1H NMR spectrum of 11 ([D8]THF, 500 MHz, Figure 7c) perature in [D6]DMSO (Figure 8) or by lowering the tem-
exhibits three different signals (two doublets at δ = 6.83 and perature in [D8]THF (Figure 7). The spectrum at 340 K
6.96 ppm and a singlet at δ = 7.11 ppm) for the protons of ([D6]DMSO, 400 MHz, Figure 8b) shows coalescence, while
the 1,4-phenylene group and reveals a parallel orientation the spectrum recorded at 400 K (Figure 8c) reveals the ra-
of the aromatic rings and hindrance to their rotation. The pid rotation of the pyridine ring at this temperature. The
protons of the four methylene groups (positions 2, 4, 11, protons of the 1,4-phenylene group denoted as 7, 8, 17 and
and 13) display eight doublets in the range from δ = 3.36 18, as well as the protons of the same methylene groups or
to 4.42 ppm, while the signals (eight doublets) correspond- the axial and equatorial protons of the different positions
ing to the axial and equatorial protons of the dioxacy- of the dioxacyclohexane rings C and D (positions 2Ј and 4Ј
clohexane rings (C and D) overlap and give a complex or 2ЈЈ and 4ЈЈ) are rendered equivalent by the dynamics of
pattern (δ = 3.19–3.36 ppm). The spectrum of 11 at 300 K the cyclophane, and the spectrum at 400 K (Figure 8c) is
in [D6]DMSO (400 MHz, Figure 8a) exhibits a similar considerably more simple than that at room-temperature.
pattern to that recorded in [D8]THF. These NMR spectra The protons of the 1,4-phenylene group exhibit an AAЈBBЈ
(recorded at room temperature) suggest the freezing of the system, the axial and equatorial protons of the two dioxacy-
rotation of the aromatic rings and the flipping of the chains clohexane rings exhibit two doublets (δ = 3.22 and
1
Figure 7. H NMR spectra (500 MHz) of compound 11 in [D8]THF at 168 (a), 210 (b), and 298 K (c).
Eur. J. Org. Chem. 2007, 4674–4687
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4681

I. Grosu et al.
FULL PAPER
3.38 ppm; differences between the dioxacyclohexane rings
The room-temperature 1H NMR spectrum (CD2Cl2, Fig-
C and D are not observed), while the protons of the four ure 9) of the N-oxide 12 is similar to the room-temperature
CH2 groups of the chains display four singlets (δ = 3.69, spectrum of 11, but the better differentiation of the signals
3.94, 4.25, and 4.27 ppm; the protons of the same CH2 pertaining to rings C and D was noticed. The variable-tem-
group are rendered equivalent by the rotation of the pyr- perature NMR experiments carried out on this compound
idine ring). A barrier of ∆G# = 16.44Ϯ0.18 kcal/mol was by increasing the temperature showed that coalescence of
calculated (using Eyring’s equations)[21] for the rotation of the signals did not occur below 400 K, so the rotation of
the aromatic rings in 11. The variable-temperature NMR the pyridine N-oxide ring is still hindered at this tempera-
experiment carried out in [D8]THF by decreasing the tem- ture. The barrier (∆G#) for the rotation of the aromatic
perature led to the observation of the coalescence of dif- rings was estimated to be higher than 20.1 kcal/mol. More
ferent signals (e.g., at 210 K, Figure 7b). The spectrum at important results were obtained by decreasing the tempera-
168 K shows clear signals and suggests the freezing of the ture; at 230 K Figure 9c), coalescence processes could be
flipping of the chains. Unfortunately, the differences in the observed. At 180 K the spectrum (Figure 9d) exhibits two
magnetic environments of similar protons in the frozen syn sets of signals belonging to the syn (major) and anti iso-
and anti structures are insignificant, and in the low-tem- mers. The ratio between the syn and anti isomers calculated
perature spectrum (168 K) the signals belonging to the syn from the low-temperature NMR spectrum is 1.60:1.00,
and anti isomers are not separated. The ratio of the two which is in good agreement with the value (syn/anti =
isomers and the barrier for the flipping of the chains could 1.69:1.00) obtained by molecular modeling. By using the
not be calculated from these experiments. However, the data obtained from the variable-temperature NMR spectra
modifications to the spectra caused by lowering the tem- and Eyring’s equations,[21] we calculated the barrier (∆G# =
perature (individual signals at room temperature, coalesc- 10.4Ϯ0.5 kcal/mol) for the flipping of the bridges
ence at 210 K, and again individual signals at 168 K) shows (Scheme 4), the experimental value being somewhat smaller
clearly the freezing of the second conformational equilib- than the one calculated by molecular modeling (∆G#
=
rium which corresponds to the flipping of the bridges.
14.04 kcal/mol).
1
Figure 8. H NMR spectra (400 MHz) of compound 11 in [D6]DMSO at 300 (a), 340 (b), and 400 K (c).
4682
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Eur. J. Org. Chem. 2007, 4674–4687

New [4.4]Cyclophane Diketals, Monoketones, and Diketones
1
Figure 9. H NMR spectra (fragments, 500 MHz) of compound 12 in [D6]DMSO at 400 K (a) and in CD2Cl2 at 303 (b), 230 (c), and
180 K (d).
1
The H NMR spectra of compound 14 reveal the hin- 13 (δ = 5.62 ppm), and a quite incredible position of this
drance of the rotation of the aromatic groups. Positions 2Ј signal (δ = 4.96 ppm) in the spectrum of diketone 15. The
and 4Ј (Table 2) of the saturated heterocycle give different shielding of the signal for this proton is important and com-
signals (δax = 3.17 and 3.21 ppm; δeq = 3.31 and 3.35 ppm), parable with spectacular cases presented in the litera-
so they are diastereotopic. The protons of the same CH2 ture.[3a,22]
group are diastereotopic as well as the protons of the four
CH2 groups of the chains which exhibit eight doublets (as
in the case of 11 and 12). The difficulties encountered in
the hydrolysis of the 1,3-dioxane rings are due to the con-
Conclusions
traction of the cyclophane when carbonyl groups are gener-
X-ray diffraction, NMR spectroscopy, and molecular-
ated (sp3 carbon atoms are replaced by sp2 carbon atoms). modeling-based structural analysis of the new [4.4]cy-
The new geometries induced by the sp2 carbon atoms bring clophanes 6–9 and 11–16 have revealed important C–H–π
closer the aromatic units of the cyclophanes (molecular (for 6, 7, 13, and 15) and π–π (for 9 and 14) stacking inter-
modeling results are shown in the Supporting Information). actions either in the solid state or in solution. The rotation
It is worth comparing the distances between the ortho,orthoЈ of the aromatic groups and the flipping of the bridges for
hydrogen atoms of ring B and the center of ring A in the some of these compounds were monitored step-by-step by
edge-tilted-to-face structures of 7 and 15 which are 3.078 variable-temperature NMR experiments. The higher barrier
and 2.617 Å, respectively, and also to compare the chemical for the rotation of the aromatic rings than for the flipping
shifts of the pertinent protons of 7, 13, and 15. The 1H of the bridges and the preference of 7, 11, and 12 for syn
NMR spectra of these compounds (Figure 10) reveal a structures were revealed. The good correlation between the
shielding of the ortho,orthoЈ protons in 7 (δ = 6.28 ppm), a calculated (using molecular modeling data) and experimen-
greater shielding of more than 0.5 ppm in the monoketone tal (based on low-temperature NMR spectra) ratios of the
Eur. J. Org. Chem. 2007, 4674–4687
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4683

I. Grosu et al.
FULL PAPER
by frequency analysis (at the same level of theory), which showed
that both transition states (TS 7B and TS 8B; discussed in the
Supporting Information) are genuine ones (i.e., they have only one
imaginary frequency and the corresponding normal modes are re-
lated to the rotation of ring B). B3LYP/6-31G(d) geometry optimi-
zations of 6, 7 (anti, syn), 8, 11 (anti, syn), 12 (anti, syn), 13 (anti,
syn), and 15 (anti, syn) were carried out and the corresponding
equilibrium geometries are shown in the Supporting Information.
However, due to the size of these systems, no further frequency
calculations were undertaken. CCDC-241320 (for 6), -273535 (for
7), -255757 (for 9), and -278082 (for 15) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
General Procedure for the Synthesis of [4.4]Cyclophanes 6–9 and 11:
Diol 5 (250 mg, 0.68 mmol) in dry THF (10 mL) was added, under
argon, to a suspension of NaH (65 mg, 2.72 mmol) in dry THF
(400 mL). The mixture was refluxed and dibrominated compounds
1–4 or 10 (0.68 mmol) dissolved in THF (80 mL) were added to
the solution over 4 d, under reflux, using a sensitive push-syringe.
Refluxing of the solvent was continued for an additional 1 d, after
which the system was cooled to room temp. and the solid phase
removed by filtration. The solvent was evaporated, and the crude
product was dissolved in CH2Cl2 (20 mL) and then washed twice
with water (20 mL). After drying with MgSO4, the solvent was re-
moved and the crude product was purified by flash chromatog-
raphy.
1
Figure 10. H NMR spectra (CDCl3, 300 MHz) at room temp. of
compounds 7 (a), 13 (b), and 15 (c).
syn and anti isomers of 12 was noticed. Dioxo[4.4]cy-
clophanes 15 and 16 could be obtained in good overall
yields starting from simple compounds and by using an
original strategy (with CAN and HCl) for the deprotection
of the cyclic ketals.
5,5,10,10-Bis(3Ј,3Ј-dimethyl-1Ј,5Ј-dioxapentane-1Ј,5Ј-diyl)-3,12-
dioxatricyclo[12.4.26,9.01,14]icosa-1(18),6,8,14,16,19-hexaene (6):
White crystals, yield 34% (107 mg, 0.28 mmol), m.p. 210–211 °C.
Purified by flash chromatography (silica gel, diethyl ether/pentane
1
= 2:3), Rf = 0.44. H NMR (300 MHz, CDCl3): δ = 0.67 (s, 6 H,
3Ј-CH3eq), 1.30 (s, 6 H, 3Ј-CH3ax), 3.46 (s, 4 H, 4-H, 11-H), 3.51
(d, 2J = 10.9 Hz, 4 H, 2Ј-Hax, 4Ј-Hax), 3.53 (s, 4 H, 2-H, 13-H),
3.72 (d, 2J = 10.9 Hz, 4 H, 2Ј-Heq, 4Ј-Heq), 7.15 (m, 2 H, 16-H, 17-
H), 7.29 (m, 2 H, 15-H, 18-H), 7.41 (s, 4 H, 7-H, 8-H, 19-H, 20-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.0 (3Ј-CH3eq), 23.0
(3Ј-CH3ax), 30.8 (C-3Ј), 70.5 (C-4, C-11), 71.9 (C-2Ј, C-4Ј), 78.4 (C-
2, C-13), 101.2 (C-5, C-10), 127.4 (C-15, C-18), 128.3 (C-16, C-17),
129.0 (C-7, C-8, C-19, C-20), 135.0 (C-6, C-9), 137.6 (C-1, C-14)
ppm. MS (EI, 70 eV): m/z (%) = 468 (2) [M]+, 438 (30), 317 (10),
204 (42), 104 (100), 69 (96). C28H36O6 (468.58): calcd. C 71.77, H
7.74; found C 71.89, H 7.68.
Experimental Section
General Experimental Data: Chemicals were purchased from Ald-
rich or Acros and were used without further purification. Unless
1
otherwise stated, routine H (300 MHz) and 13C NMR (75 MHz)
spectra, COSY, HMQC, and HMBC were recorded at room temp.
in CDCl3 with a Bruker 300 MHz spectrometer using the solvent
line as reference. Variable-temperature NMR and NOESY spectra
were recorded with a Bruker 400, 500, or 600 MHz spectrometer,
respectively, in CDCl3, CD2Cl2, [D8]THF, or [D6]DMSO. The FID
was retreated by applying a Gaussian curve (GB 0.2 and LB-5) in
the cases of 11–13. Melting points were measured with a Kleinfeld
melting-point apparatus and are uncorrected. Microanalyses (C, H,
N) agreed (within Ϯ0.4%) with calculated data. Mass spectra were
recorded with an ATI Unicam Automass fitted spectrometer. Thin-
layer chromatography (TLC) was conducted on silica gel 60 F254
TLC plates purchased from Merck. Preparative column (flash)
chromatography was preformed using PharmPrep 60 CC (40–
63 µm) silica gel purchased from Merck. The calculations were car-
ried out by using the Spartan04 (Spartan’04 Wavefunction, Inc.,
Irvine, CA) suite of programs. Energy profiles for the rotation of
ring B against ring A were constructed at the PM3 level of theory
by constraining the specific dihedrals (which define the motion of
the ring) and fully optimizing the rest of coordinates.[23] Bridge
flipping was similarly treated by restraining the rotations around
the bridging O–CH2 single bonds and by fully optimizing the re-
maining coordinates. In order to check the validity of the PM3
results, the B3LYP hybrid density functional with the 6-31G(d) ba-
sis set[24] was used to search for the transition state for rotation of
ring B in 7 and 8. The nature of the stationary points was checked
5,5,10,10-Bis(3Ј,3Ј-dimethyl-1Ј,5Ј-dioxapentane-1Ј,5Ј-diyl)-3,12-di-
oxatricyclo[12.3.26,9.11,14]icosa-1(20),6,8,14,16,18-hexaene (7):
White crystals, yield 49% (156 mg, 0.33 mmol), m.p. 217–218 °C.
Purified by flash chromatography (silica gel, diethyl ether/pentane
1
= 2:3), Rf = 0.62. H NMR (300 MHz, CDCl3): δ = 0.65 (s, 6 H,
2
3Ј-CH3eq), 1.29 (s, 6 H, 3Ј-CH3ax), 3.47 (d, J = 10.6 Hz, 4 H, 2Ј-
2
Hax, 4Ј-Hax), 3.57 (s, 4 H, 4-H, 11-H), 3.63 (d, J = 10.6 Hz, 4 H,
2Ј-Heq, 4Ј-Heq), 4.30 (s, 4 H, 2-H, 13-H), 6.28 (s, 1 H, 20-H), 6.85
3
3
(d, J = 7.5 Hz, 2 H, 15-H, 17-H), 6.99 (t, J = 7.5 Hz 1 H, 16-H),
7.33 (s, 4 H, 7-H, 8-H, 18-H, 19-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 22.1 (3Ј-CH3eq) 23.0 (3Ј-CH3ax), 30.7 (C-3Ј), 71.7 (C-
2Ј, C-4Ј), 72.6 (C-2, C-13), 77.2 (C-4, C-11), 100.6 (C-5, C-10),
126.9 (C-16), 127.3 (C-15, C-17), 128.0 (C-7, C-8, C-18, C-19),
128.4 (C-20), 137.3 (C-6, C-9), 137.9 (C-1, C-14) ppm. MS (EI,
70 eV): m/z (%) = 468 (0.4) [M]+, 438 (69), 408 (7), 190 (19), 149
(9), 104 (100), 69 (62). C28H36O6 (468.58): calcd. C 71.77, H 7.74;
found C 71.81, H 7.66.
5,5,10,10-Bis(3Ј,3Ј-dimethyl-1Ј,5Ј-dioxapentane-1Ј,5Ј-diyl)-3,12-di-
oxatricyclo[12.2.26,9.21,14]icosa-1(20),6,8,14(19),15,17-hexaene (8):
4684
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New [4.4]Cyclophane Diketals, Monoketones, and Diketones
White crystals, yield 67% (215 mg, 0.46 mmol), m.p. 219–220 °C.
solution of 11 (80 mg, 0.17 mmol) in dichloromethane (5 mL) at
0 °C and the mixture was stirred at this temperature for 45 min.
Then the reaction mixture was successively washed with saturated
Purified by flash chromatography (silica gel, diethyl ether/pentane
1
= 1:1), Rf = 0.37. H NMR (300 MHz, CDCl3): δ = 0.55 (s, 6 H,
2
3Ј-CH3eq), 1.23 (s, 6 H, 3Ј-CH3ax), 3.31 (d, J = 10.6 Hz, 4 H, 2Ј- NaHCO3 (3 ϫ 10 mL) and brine (10 mL). After drying with
2
Hax, 4Ј-Hax), 3.37 (d, J = 10.6 Hz, 4 H, 2Ј-Heq, 4Ј-Heq), 3.78 (s, 4 MgSO4, the solvent was removed and the crude product was puri-
H, 4-H, 11-H), 4.27 (s, 4 H, 2-H, 13-H), 6.87 (s, 4 H, 7-H, 8-H, 17-
H, 18-H), 7.02 (s, 4 H, 15-H, 16-H, 19-H, 20-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 22.1 (3Ј-CH3eq) 22.9 (3Ј-CH3ax), 30.5 (C-3Ј),
71.3 (C-2Ј, C-4Ј), 73.4 (C-2, C-13), 76.0 (C-4, C-11), 99.5 (C-5, C-
10), 127.7 (C-15, C-16, C-19, C-20), 129.7 (C-7, C-8, C-17, C-18),
136.5 (C-6, C-9), 136.6 (C-1, C-14) ppm. MS (EI, 70 eV): m/z (%)
= 469 (2) [M]+, 438 (59), 190 (30), 149 (15), 104 (100), 69 (96).
C28H36O6 (468.58): calcd. C 71.77, H 7.74; found C 71.77, H 7.67.
fied by flash chromatography.
16-Oxo-5,5,10,10-bis(3Ј,3Ј-dimethyl-1Ј,5Ј-dioxapentane-1Ј,5Ј-diyl)-
3,12-dioxa-16-azatricyclo[12.2.26,9.21,14]icosa-1(20),6(17),7,9(19),
14,15-hexaene (12): White crystals, yield 83% (68 mg, 0.14 mmol),
m.p. 235–236 °C. Purified by flash chromatography (silica gel,
dichloromethane/methanol = 2:0.1), Rf = 0.4. 1H NMR (300 MHz,
CDCl3): δ = 0.560 (s, 6 H, 3Ј-CH3eq, 3ЈЈ-CH3eq), 1.20 (s, 6 H, 3Ј-
CH3ax, 3ЈЈ-CH3ax), 3.23–3.39 (overlapped signals, 8 H, 2Ј-Hax, 4Ј-
2
Hax, 2ЈЈ-Hax, 4ЈЈ-Hax, 2Ј-Heq, 4Ј-Heq, 2ЈЈ-Heq, 4ЈЈ-Heq), 3.65 (d, J
5,5,10,10-Bis(3Ј,3Ј-dimethyl-1Ј,5Ј-dioxapentane-1Ј,5Ј-diyl)-3,12-di-
oxatetracyclo[12.6.26,9.21,14.015,20]tetracosa-1(24),6,8,14(23),15,
17,19,21-octaene (9): White crystals, yield 52 % (183 mg,
0.35 mmol), m.p. 238–239 °C. Purified by flash chromatography
(silica gel, diethyl ether/pentane = 1:2), Rf = 0.31. 1H NMR
(300 MHz, CDCl3): δ = 0.46 (s, 6 H, 3Ј-CH3eq), 1.20 (s, 6 H, 3Ј-
2
= 9.8 Hz 1 H, 11-CHH), 3.87 (d, J = 9.8 Hz 1 H, 11-CHH), 4.02
(d, 2J = 10.2 Hz, 1 H, 4-CHH), 4.10 (d, 2J = 12.8 Hz, 1 H, 2-
CHH), 4.13 (d, 2J = 12.5 Hz, 13-CHH), 4.28 (d, 2J = 12.5 Hz, 1
2
2
H, 13-CHH), 4.49 (d, J = 10.2, 1 H, 4-CHH), 5.25 (d, J = 12.8,
3
4
1 H, 2-CHH), 6.77 (dd, J = 7.9, J = 1.5 Hz, 1 H, 19-H), 6.91 (d,
3J = 7.9 Hz, 1 H, 20-H), 7.07 (dd, J = 8.2, J = 1.9 Hz, 1 H, 18-
3
4
2
2
CH3ax), 3.09 (d, J = 10.9 Hz, 2 H, 2Ј-Hax), 3.14 (d, J = 10.9 Hz,
3
4
3
2
4
H), 7.15 (dd, J = 8.2, J = 1.9 Hz, 1 H, 17-H), 7.26 (dd, J = 7.9,
2 H, 4Ј-Hax), 3.26 (dd, J = 10.9, J = 2.6 Hz, 2 H, 4Ј-Heq), 3.32
4J = 1.9 Hz, 1 H, 8-H), 7.45 (dd, J = 7.9, J = 1.9 Hz, 1 H, 7-H),
7.70 (d, 4J = 1.5 Hz, 1 H, 15-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 22.08 [3Ј(3ЈЈ)-CH3eq]*, 22.18 [3Ј(3ЈЈ)-CH3eq]*, 22.89 [3Ј(3ЈЈ)-
CH3ax]*, 22.92 [3Ј(3ЈЈ)-CH3ax]*, 30.4 (C-3Ј, C-3ЈЈ), 65.8 (C-2), 70.3
(C-13), 71.2, 71.39, 71.44, 71.48 (C-2Ј, C-4Ј, C-2ЈЈ, C-4ЈЈ)*, 77.3
(C-11), 79.1 (C-4), 99.2 (C-10), 99.6 (C-5), 126.0 (C-19), 126.7 (C-
18), 127.2 (C-20), 127.5 (C-7), 128.4 (C-8), 128.9 (C-17), 135.1 (C-
9), 136.5 (C-6), 137.4 (C-14), 140.6 (C-15), 147.4 (C-1) ppm; *unas-
signed signals. MS (EI, 70 eV): m/z (%) = 485 (1.1) [M]+, 440 (44),
233 (11), 190 (24), 149 (16), 104 (68), 69 (100). C27H35NO7 (485.57):
calcd. C 66.79, H 7.27, N 2.88; found C 66.92, H 7.43, N 2.71.
3
4
2
4
2
(dd, J = 10.9, J = 2.6 Hz, 2 H, 2Ј-Heq), 3.52 (d, J = 10.0 Hz, 2
H, 4-CHH, 11-CHH), 4.09 (d, 2J = 12.8 Hz, 2 H, 2-CHH, 13-
2
2
CHH), 4.22 (d, J = 10.0 Hz, 2 H, 4-CHH, 11-CHH), 5.44 (d, J
4
= 12.8 Hz, 2 H, 2-CHH, 13-CHH), 6.05 (d, J = 1.1 Hz, 2 H, 7-H,
8-H), 6.75 (s, 2 H, 23-H, 24-H), 7.02 (d, J = 1.1 Hz, 2 H, 21-H,
4
22-H), 7.58 (m, 2 H, 17-H, 18-H), 8.21 (m, 2 H, 16-H, 19-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 22.0 (3Ј-CH3eq), 22.9 (3Ј-CH3ax),
30.4 (C-3Ј), 71.2 (C-2Ј, C-4Ј), 72.2 (C-2, C-13), 76.0 (C-4, C-11),
99.3 (C-5, C-10), 125.5 (C-16, C-19), 125.8 (C-23, C-24), 126.0 (C-
17, C-18), 126.8 (C-21, C-22), 127.2 (C-7, C-8), 133.0 (C-15, C-20),
134.3 (C-1, C-14), 136.4 (C-6, C-9) ppm. MS (EI, 70 eV): m/z (%)
= 518 (3.6) [M]+, 488 (100), 190 (41), 154 (21), 104 (63), 69 (89).
C32H38O6 (518.64): calcd. C 74.11, H 7.39; found C 74.29, H 7.20.
General Procedure for the Synthesis of [4.4]Cyclophanes 13 and 14:
Solid cerium ammonium nitrate (CAN, 12 mg, 10 mol-%) was
added to a stirred solution of compound 7 or 9 (0. 214 mmol) in
MeCN (3 mL) and water (3 mL). The solution was refluxed for
12 h. After cooling to room temperature, water (5 mL) was added
and the mixture was extracted with dichloromethane (3ϫ10 mL).
The organic layers were dried with MgSO4, filtered, and the solvent
was evaporated in vacuo. The crude product was further purified
by flash chromatography.
5,5,10,10-Bis(3Ј,3Ј-dimethyl-1Ј,5Ј-dioxapentane-1Ј,5Ј-diyl)-3,12-di-
oxa-16-azatricyclo[12.2.26,9.21,14]icosa-1(20),6(17),7,9,14(19),15-
hexaene (11): White crystals, yield 43% (138 mg, 0.29 mmol), m.p.
164–165 °C. Purified by flash chromatography (silica gel, dichloro-
methane/methanol = 4:0.1), Rf = 0.25. 1H NMR (300 MHz,
CDCl3): δ = 0.560 [s, 3 H, 3Ј(3ЈЈ)-CH3eq]*, 0.564 [s, 3 H, 3Ј(3ЈЈ)-
CH3eq],* 1.23 (s, 6 H, 3Ј-CH3ax, 3ЈЈ-CH3ax), 3.33–3.43 (overlapped
signals, 8 H, 2Ј-Hax, 4Ј-Hax, 2ЈЈ-Hax, 4ЈЈ-Hax, 2Ј-Heq, 4Ј-Heq, 2ЈЈ-
Heq, 4ЈЈ-Heq), 3.49 (d, 2J = 9.6 Hz, 1 H, 11-CHH), 3.89 (d, 2J =
9.6 Hz, 1 H, 11-CHH), 4.02 (d, 2J = 9.6 Hz, 1 H, 4-CHH), 4.10 (d,
5-Oxo-10,10-(3Ј,3Ј-dimethyl-1Ј,5Ј-dioxapentane-1Ј,5Ј-diyl)-3,12-di-
oxatricyclo[12.3.26,9.11,14]icosa-1(20),6,8,14,16,18-hexaene (13):
White crystals, yield 74% (60 mg, 0.15 mmol), m.p. 184–185 °C.
Purified by flash chromatography (silica gel, diethyl ether/pentane
2
2J = 12.5 Hz, 1 H, 13-CHH), 4.11 (d, J = 9.6 Hz, 4-CHH), 4.27
(d, 2J = 12.0 Hz, 1 H, 2-CHH), 4.49 (d, 2J = 12.5 Hz, 1 H, 13-
1
= 2:3), Rf = 0.60. H NMR (300 MHz, CDCl3): δ = 0.63 (s, 3 H,
2
3
2
CHH), 4.50 (d, J = 12.0 Hz, 1 H, 2-CHH), 6.90 (d, J = 7.5 Hz,
3Ј-CH3eq), 1.29 (s, 3 H, 3Ј-CH3ax), 3.49 (d, J = 11.2 Hz, 2 H, 2Ј-
3
3
Hax, 4Ј-Hax), 3.56 (s, 2 H, 11-H), 3.59 (d, 2J = 11.2 Hz, 2 H, 2Ј-
Heq, 4Ј-Heq), 4.11 (s, 2 H, 13-H), 4.34 (s, 2 H, 2-H), 5.53 (s, 2 H,
1 H, 20-H), 6.92 (d, J = 8.0 Hz, 1 H, 8-H), 7.03 (d, J = 8.0 Hz,
1 H, 7-H), 7.19 (s, 2 H, 17-H, 18-H), 7.21 (dd, 3J = 7.5, 4J = 2.6 Hz,
1 H, 19-H), 8.04 (d, 4J = 2.6 Hz, 1 H, 15-H) ppm; *unassigned
signals. 13C NMR (75 MHz, CDCl3): δ = 22.08 [3Ј(3ЈЈ)-CH3eq]*,
22.12 [3Ј(3ЈЈ)-CH3eq]*, 22.95 [3Ј(3ЈЈ)-CH3ax]*, 22.99 [3Ј(3ЈЈ)-
CH3ax]*, 30.5 (C-3Ј, C-3ЈЈ), 70.8 (C-13), 71.2, 71.3, 71.4 (C-2Ј, C-
4Ј, C-2ЈЈ, C-4ЈЈ),* 73.8 (C-2), 75.9 (C-11), 76.4 (C-4), 99.4 (C-10),
99.5 (C-5), 123.0 (C-20), 126.6 (C-8), 127.4 (C-17), 128.4 (C-18),
128.6 (C-7), 130.9 (C-14), 136.3 (C-9), 137.04 (C-6), 137.08 (C-19),
150.9 (C-15), 156.3 (C-1) ppm; *unassigned signals. MS (EI,
70 eV): m/z (%) = 469 (3) [M]+, 439 (89), 303 (9), 190 (19), 104
(84), 69 (100). C27H35NO6 (469.57): calcd. C 69.06, H 7.51, N 2.98;
found C 68.88, H 7.70, N 3.07.
3
4
4-H), 5.62 [t, (dd overlapped), 1 H, 20-H], 6.91 (dt, J = 7.2, J =
1.5 Hz, 1 H, 15-H), 7.05 (dt, 3J = 7.5, 4J = 1.5 Hz, 1 H, 17-H),
3
7.12 [t, (dd overlapped), 1 H, 16-H), 7.49 (d, J = 8.3 Hz, 2 H, 8-
3
H, 18-H), 7.74 (d, J = 8.3 Hz, 2 H, 7-H, 19-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 22.0 (3Ј-CH3eq), 23.0 (3Ј-CH3ax), 30.7 (C-
3Ј), 71.9 (C-2Ј, C-4Ј), 72.6 (C-2), 73.1 (C-13), 75.8 (C-4), 76.7 (C-
11), 100.5 (C-10), 127.3 (C-16), 127.8 (C-15, C-17), 128.0 (C-20),
128.5 (C-8, C-18), 129.1 (C-7, C-19), 136.2 (C-1), 136.8 (C-14),
138.3 (C-6), 142.6 (C-9), 205.7 (C-5) ppm. MS (FAB+): m/z (%) =
383 (14) [M + H]+. C23H26O5 (382.45): calcd. C 72.23, H 6.85;
found C 72.37, H 6.73.
Procedure for the Synthesis of Compound 12: m-Chloroperoxyben-
zoic acid (70%, 41.89 mg, 0.17 mmol) was added portionwise to a
5-Oxo-10,10-(3Ј,3Ј-dimethyl-1Ј,5Ј-dioxapentane-1Ј,5Ј-diyl)-3,12-di-
oxatetracyclo[12.6.26,9.21,14.015,20]tetracosa-1(24),6,8,14(23),15,
Eur. J. Org. Chem. 2007, 4674–4687
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4685

I. Grosu et al.
FULL PAPER
17,19,21-octaene (14): White crystals, yield 51% (42 mg, 0.1 mmol),
m.p. 191–192 °C. Purified by flash chromatography (silica gel, di-
ethyl ether/pentane = 2:3), Rf = 0.44. 1H NMR (300 MHz, CDCl3):
Acknowledgments
The Agence Universitaire de la Francophonie (AUF) and Le Con-
seil Géneral de la Région Haute-Normandie are gratefully ac-
knowledged for the fellowships given to N. B. The Consiliul
National al Cercetarii Stiintifice din Invatamantul Superior
(CNCSIS) and Unitatea Executiva pentru Finantarea Invataman-
tului Superior si a Cercetarii Stiintifice Universitare (UEFISCSU)
are acknowledged for the financial support of this work (grants
A1315/2006 and ET 48).
2
δ = 0.48 (s, 3 H, 3Ј-CH3eq), 1.21 (s, 3 H, 3Ј-CH3ax), 3.16 (d, J =
11.3 Hz, 1 H, 2Ј-Hax), 3.22 (d, 2J = 10.9 Hz, 1 H, 4Ј-Hax), 3.30 (dd,
2J = 11.3, 4J = 2.6 Hz, 1 H, 2Ј-Heq), 3.37 (dd, 2J = 10.9, 4J =
2.6 Hz, 1 H, 4Ј-Heq), 3.49 (d, 2J = 10.0 Hz, 1 H, 11-CHH), 4.06 (d,
2J = 13.2 Hz, 1 H, 13-CHH), 4.10 (d, 2J = 10.0 Hz, 1 H, 11-CHH),
2
2
4.57 (d, J = 15.6 Hz, 1 H, 2-CHH), 4.70 (d, J = 13.0 Hz, 1 H, 4-
2
2
CHH), 4.75 (d, J = 15.6 Hz, 1 H, 2-CHH), 5.33 (d, J = 13.2 Hz,
1 H, 13-CHH), 5.37 (d, 2J = 13.0 Hz, 1 H, 4-CHH), 6.49 (dd, 3J =
4
3
4
7.9, J = 1.8 Hz, 1 H, 22-H), 6.52 (dd, J = 7.9, J = 1.8 Hz, 1 H,
21-H), 6.80 (d, 3J = 6.8 Hz, 1 H, 23-H), 6.99 (dd, 3J = 8.1, 4J =
1.8 Hz, 1 H, 8-H), 7.02 (d, J = 6.8 Hz, 1 H, 24-H), 7.51 (dd, J =
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4
8.1, J = 1.8 Hz, 1 H, 7-H), 7.53–7.57 (m, overlapped peaks, 2 H,
C-17, C-18), 8.01–8.04 (m, 2 H, C-16, C-19) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.8 (3Ј-CH3eq), 22.8 (3Ј-CH3ax), 30.5 (C-
3Ј), 71.50 (C-2Ј), 71.56 (C-4Ј), 71.9 (C-13), 73.2 (C-4), 77.7 (C-2),
78.6 (C-11), 99.8 (C-10), 124.4, 125.5, 126.27, 126.29, 126.5, 126.8,
127.1, 127.8, 128.1, 128.8 (C-7, C-8, C-16, C-17, C-18, C-19, C-21,
C-22, C-23, C-24),* 132.4, 132.6, 133.6, 135.2, 135.3 (C-9, C-14, C-
15, C-16, C-20),* 141.6 (C-6), 200.7 (C-5) ppm; *unassigned sig-
nals. MS (EI, 70 eV): m/z (%) = 432 (10) [M]+, 402 (100), 233 (49),
190 (54), 141 (50), 104 (86), 69 (62). C27H28O5 (432.19): calcd. C
74.98, H 6.53; found C 74.77, H 6.67.
General Procedure for the Synthesis of Diketones 15 and 16: Solid
cerium ammonium nitrate (CAN, 5 mg, 10 mol-%) and 6  HCl
(0.01 mL) were added to a stirred solution of compound 7 or 8
(50 mg, 0.1 mmol) in MeCN (3 mL) and water (1 mL). The solu-
tion was refluxed for 6 h. After cooling to room temperature, water
(5 mL) was added and the mixture was extracted with dichloro-
methane (3ϫ10 mL). The organic layers were dried with MgSO4,
filtered, and the solvent was evaporated in vacuo. The crude prod-
uct was further purified by flash chromatography.
5,10-Dioxo-3,12-dioxatricyclo[12.3.26,9.11,14]icosa-1(20),6,8,14,
16,18-hexaene (15): White crystals, yield 84% (27 mg, 0.09 mmol),
m.p. 179–180 °C. Purified by flash chromatography (silica gel, di-
ethyl ether/pentane = 2:3), Rf = 0.43. 1H NMR (300 MHz, CDCl3):
δ = 4.14 (s, 4 H, 2-H, 13-H), 4.54 (s, 4 H, 4-H, 11-H), 4.96 (s, 1 H,
20-H), 7.10–7.12 (overlapped peaks, 2 H, 15-H, 17-H), 7.21 (dd, 3J
3
= 8.3, J = 8.7 Hz, 1 H, 16-H), 7.81 (s, 4 H, 7-H, 8-H, 18-H, 19-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 73.3 (C-2, C-13), 76.0
(C-4, C-11), 128.4 (C-16), 128.5 (C-15, C-17), 129.2 (C-7, C-8, C-
18, C-19), 131.3.1 (C-20), 136.7 (C-1, C-14), 139.2 (C-6, C-9), 205.2
(C-5, C-10) ppm. MS (FAB+): m/z (%) = 297 (14) [M + H]+.
C18H16O4 (296:32): calcd. C 72.96, H 5.54; found C 72.81, H 5.67.
5,10-Dioxo-3,12-dioxatricyclo[12.2.26,9.21,14]icosa-1(20),6,8,14(19),
15,17-hexaene (16): White crystals, yield 92% (29 mg, 0.01 mmol),
m.p. 172–173 °C. Purified by flash chromatography (silica gel, di-
ethyl ether/pentane = 1:2), Rf = 0.23. 1H NMR (300 MHz, CDCl3):
δ = 4.49 (s, 4 H, 2-H, 13-H), 4.60 (s, 4 H, 4-H, 11-H), 6.81 (s, 4 H,
15-H, 16-H, 19-H, 20-H), 7.47 (s, 4 H, 7-H, 8-H, 17-H, 18-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 75.9 (C-2, C-13), 77.6 (C-4, C-
11), 128.7 (C-7, C-8, C-17, C-18), 129.3 (C-15, C-16, C-19, C-20),
137.8 (C-1, C-14), 138.9 (C-6, C-9), 201.4 (C-5, C-10) ppm. MS
(EI, 70 eV): m/z (%) = 296 (0.5) [M]+, 266 (4), 236 (26), 147 (39),
132 (53), 119 (18), 104 (100), 91 (71), 76 (62), 63 (14). C18H16O4
(296:32): calcd. C 72.96, H 5.54; found C 72.79, H 5.58.
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Supporting Information (see footnote on the first page of this arti-
cle): Synthesis, procedures and characterization of the precursors,
NMR determination of the barriers of rotation, X-ray determi-
nation data, results of the molecular modeling.
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4674–4687

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and planar chirality are introduced into the molecule. If the
other hydrogen atom of the considered CH2 group is changed,
the same chiral elements are introduced into the molecule. The
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the same for both substituted derivatives. The substitution test
leads to diastereoisomers, so the protons of the considered CH2
group are diastereotopic. It is a peculiar case in which protons
of a CH2 group pertaining to an achiral molecule (without ste-
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Received: April 18, 2007
Published Online: July 27, 2007
Eur. J. Org. Chem. 2007, 4674–4687
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4687