Conformational Studies by Dynamic NMR. 97.1 Structure, Conformation, Stereodynamics and Enantioseparation of Aryl Substituted Norbornanes

Article abstract of DOI:10.1021/jo035411n

The structure of a 1,7,7-triaryl norbornane (compound 3) has been determined by X-ray diffraction and was found essentially equal to that predicted by molecular mechanics calculations. Restricted rotation of the aryl groups also has been observed by dynam

Full text of DOI:10.1021/jo035411n

Con for m a tion a l Stu d ies by Dyn a m ic NMR. 97.1 Str u ctu r e,
Con for m a tion , Ster eod yn a m ics a n d En a n tiosep a r a tion of Ar yl
Su bstitu ted Nor bor n a n es
Daniele Casarini*
Department of Chemistry, University of Basilicata, Potenza, Italy
Stefano Grilli, Lodovico Lunazzi, and Andrea Mazzanti*
Department of Organic Chemistry “A.Mangini”, University of Bologna,
Viale Risorgimento, 4 Bologna 40136, Italy
mazzand@ms.fci.unibo.it
Received September 26, 2003
The structure of a 1,7,7-triaryl norbornane (compound 3) has been determined by X-ray diffraction
and was found essentially equal to that predicted by molecular mechanics calculations. Restricted
rotation of the aryl groups also has been observed by dynamic NMR spectroscopy in this compound
and in a number of analogously substituted norbornanes. The aryl-norbornane bond rotation
barriers were measured by line shape analysis of the 13C NMR spectra obtained at temperatures
lower than -100 °C and were found to cover the range 6.0 to 7.9 kcal mol-1. An exception was the
rotation involving the o-anisyl group in compound 5, which occurs near ambient temperature since
the corresponding barrier is much higher (14.4 kcal mol-1). In one case (compound 4) configurational
enantiomers could be separated by chiral HPLC and the corresponding CD spectra recorded.
In tr od u ction
of low-temperature NMR spectroscopy, Molecular Me-
chanics calculations, and X-ray diffraction.
The importance of studies concerning the arene-arene
2
interactions recently has been pointed out again by
Martinez and co-workers who, for this purpose, investi-
gated a number of 7,7-diaryl-substituted norbornanes.3,4
In particular they were able to measure the rotation
barriers about the aryl-carbon bond when the aryl is a
phenyl group bearing a fluorine substituent in the ortho
position.3 Subsequently we could also determine the
much lower barriers occurring in the analogous 9,9-diaryl
biciclononanes.5 We have now extended our studies to
the case of 7,7-diaryl-substituted norbornanes that do not
necessarily bear an ortho substituent in the aryl group.
In particular we investigated norbornanes 1-5 by means
(1) (a) Part 96: Grilli, S.; Lunazzi, L.; Mazzanti, A.; Pinamonti, M.
Tetrahedron Symposium in Print. Submitted for publication. (b) Part
95: Anderson, J . E.; de Meijere, A.; Kozhushkov, S. I.; Lunazzi, L.;
Mazzanti, A. J . Org. Chem. 2003, 68, 8494. (c) Part 94: Coluccini, C.;
Grilli, S.; Lunazzi, L.; Mazzanti, A. J . Org. Chem., 2003, 68, 7266.
(2) (a) Cozzi, F.; Cinquini, M.; Annunziata, R.; Siegel, J . S. J . Am.
Chem. Soc. 1993, 115, 5330. (b) Cozzi, F.; Ponzini, F.; Cinquini, M.;
Annunziata, R.; Cinquini, M.; Siegel, J . S. Angew. Chem., Int. Ed. Engl.
1995, 34, 1019. (c) J ennings, W. B.; Farrell, B. M.; Malone, J . F. Acc.
Chem. Res. 2001, 34, 885. (d) Carver, F. J .; Hunter, C. A.; Livingstone,
D. J .; McCabe, J . F.; Seward, E. M. Chem. Eur. J . 2002, 8, 2847. (e)
Cozzi, F.; Annunziata, R.; Benaglia, M.; Cinquini, M.; Raimondi, L.;
Baldridge, K. K.; Siegel, J . S. Org. Biomol. Chem. 2003, 157. (f) Meyer,
E. A.; Castellano, R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003,
42, 1210.
Resu lts a n d Discu ssion
Theoretical MM calculations (MMX force field6) carried
out for compound 1 indicate that the ground-state
conformation has the two phenyl rings in an apical
cofacial3 relationship (as shown in Figure 1), which does
not display the propeller-like shape exhibited by the
diaryl methane derivatives.7
The tridimensional energy surface computed as a
function of the two phenyl-C7 bond angles (Figure 1)
(3) Martinez, A. G.; Barcina, J . O.; Cerezo, A. de F.; Rivas, R. G. J .
Am. Chem. Soc. 1998, 120, 673.
(4) (a) Martinez, A. G.; Barcina, J . O.; Albert, A.; Cano, F. H.;
Subramanian, L. R. Tetrahedron Lett. 1993, 34, 6753. (b) Martinez,
A. G.; Barcina, J . O.; Cerezo, A. de F. Chem. Eur. J . 2001, 7, 1171.
(5) Casarini, D.; Rosini, C.; Grilli, S.; Lunazzi, L.; Mazzanti, A. J .
Org. Chem. 2003, 68, 1815.
(6) MMX force field as implemented in the computer package PC
Model v 6, Serena Software, Bloomington, IN.
(7) (a) Barnes, J . C.; Paton, J . D.; Damewood, J . R.; Mislow, K. J .
Org. Chem. 1981, 46, 4975. (b) Feigel, M. J . Mol. Struct. (THEOCHEM)
1996, 36, 83. (c) Grilli, S.; Lunazzi, L.; Mazzanti, A. J . Org. Chem.
2001, 66, 5853.
10.1021/jo035411n CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/19/2003
J . Org. Chem. 2004, 69, 345-351
345

Casarini et al.
F IGURE 1. Computed6 energy surface for 1 as a function of
the phenyl-C7 rotation angles ϑ1 and ϑ2. The lines describe
the pathway between the topomers visited by the rotation of
each phenyl group.
F IGURE 2. Left: 13C NMR signals (100.6 MHz) of the ortho
(o) and meta (m) carbons of the phenyl groups of 1 as a function
of temperature in CHF2Cl/CHFCl2. The 1st and 3rd lines of
the spectrum at -132 °C (129.25 and 128.8 ppm) are due to
the diastereotopic meta carbons, the 2nd and the 4th (129.1
and 128.45 ppm) to the diastereotopic ortho carbons. Right:
Computer simulation obtained with the rate constants indi-
cated.
suggests that the two phenyl rings rotate independently
of each other (in other words they do not undergo a
correlated cogwheel pathway8): the barrier for this
process is computed to be about 10 kcal mol-1. Even
allowing for the approximations involved in such com-
putations, the value for this barrier should be high
enough as to be amenable to an experimental verification
by means of dynamic NMR spectroscopy.
In Figure 2 (left) the 13C signals of the ortho and meta
carbons (unambiguously assigned9 by the HMBC se-
quence10) are reported as a function of temperature. The
two sharp single lines, observed from ambient temper-
ature until -49 °C, broaden on further cooling and each
splits into a pair of equally intense lines at -132 °C. This
is a consequence of the restricted rotation about the Ph-
C7 bond that renders diastereotopic the ortho and meta
positions, so that four lines are observed for the corre-
sponding carbons. Computer line shape simulation (Fig-
ure 2, right) yields the values of the rate constants, hence
the free energy of activation (∆Gq ) 7.9 ( 0.15 kcal
mol-1), for the rotation of the phenyl group (Table 1). As
is often observed in conformational processes, this value
TABLE 1. Exp er im en ta l Rota tion Ba r r ier s (∆Gq, (0.15
k ca l m ol-1) for Com p ou n d s 1-5
bond rotation
1
2
3
4
5
phenyl-C7
p-anisyl-C7
phenyl-C1
o-anisyl-C7
7.9
6.0
6.15
6.1
6.05
6.0
6.7
7.5
14.4
turns out to be independent of temperature, within the
experimental uncertainty.11 The difference (about 2 kcal
mol-1) between the experimental and computed barrier
is quite acceptable, given the complexity of the molecule
investigated.
When the methyl group of 1 is replaced by a phenyl
group (as in derivative 2), two rotational processes are
expected to occur, in principle, for the two types of phenyl
substituents. However, MM calculations6 indicate that
the barrier for the rotation of the phenyl in position 1 is
almost equal to that for the two phenyl groups in position
7 (depending on the approach involved in the computing
(8) (a) Mislow, K. Acc. Chem. Res. 1976, 9, 26, (b) Mislow, K.
Chemtracts Org. Chem. 1989, 2, 151. (c) Biali, S. E.; Nugiel, D. A.;
Rappoport, Z. J . Am. Chem. Soc. 1989, 111, 846. (d) Glaser, R. In
Acyclic Organonitrogen Stereochemistry; Lambert, J . B., Takeuchi, Y.,
Eds.; VCH: New York, 1992; Chapter 4, p 123. (e) Grilli, S.; Lunazzi,
L.; Mazzanti, A.; Mazzanti, G. J . Org. Chem. 2001, 66, 748 and
references quoted therein.
(9) At ambient temperature the orthocarbon line is at lower field
with respect to the meta, but moves at higher field on cooling, the
crossing point occurring at about 0 °C where the two lines are
coincident.
(11) Hoogosian, S.; Bushweller, C. H.; Anderson, W. G.; Kigsley, G.
J . Phys. Chem. 1976, 80, 643. Lunazzi, L.; Cerioni, G.; Ingold, K. U. J .
Am. Chem. Soc. 1976, 98, 7484. Bernardi, F.; Lunazzi, L.; Zanirato,
P.; Cerioni, G. Tetrahedron 1977, 33, 1337. Lunazzi, L.; Magagnoli,
C.; Guerra, M.; Macciantelli, D. Tetrahedron Lett. 1979, 3031. Ander-
son, J . E.; Tocher, D. A.; Casarini, D.; Lunazzi, L. J . Org. Chem. 1991,
56, 1731. Cremonini, M. A.; Lunazzi, L.; Placucci, G.; Okazaki, R.;
Yamamoto, G. J . Am. Chem. Soc. 1992, 114, 6521. Borghi, R.; Lunazzi,
L.; Placucci, G.; Cerioni, G.; Foresti, E.; Plumitallo, A. J . Org. Chem.
1997, 62, 4923.
(10) Claridge, T. D. W. High-Resolution NMR Techniques in Organic
Chemistry; Pergamon: Oxford, UK, 1999; Chapter 6.
346 J . Org. Chem., Vol. 69, No. 2, 2004

Conformational Studies by Dynamic NMR
procedure, the values cover the range 6.3 ( 0.4 kcal
mol-1). Such a near identity of the two barriers can be
accounted for by considering that the motion of the
phenyl bonded to C1 is essentially correlated to that of
each phenyl bonded to C7. The rotation of the phenyl
bonded to C1 simultaneously drives the rotation of the
other two phenyl rings, according to a type of cogwheel
pathway where the three rings move in unison, thus
sharing a common transition state.8 The barrier for this
process is predicted to be significantly lower than the
corresponding barrier previously computed for 1, as often
occurs when correlated motions are involved.1c The
calculations also establish that in the ground state of 2
the phenyl in position 1 adopts a disposition having the
ring essentially orthogonal to the plane of symmetry of
the molecule (the plane of this phenyl is actually com-
puted to deviate by 25° from a perfect orthogonal ar-
rangement, but a low barrier libration process12 estab-
lishes again a dynamic Cs symmetry in the NMR time
scale). For this reason the corresponding rotation is NMR
invisible since the ortho and the meta positions remain
indistinguishable, as in the conditions of fast rotation,
even when this motion is frozen: consequently a single
line for the corresponding pairs of carbons is observed
at any accessible temperature.
F IGURE 3. X-ray (top) and MM computed6 structure (bottom)
of compound 3.
The barrier involving the rotation of the two phenyl
groups bonded to C7 could be experimentally determined,
yielding a value (6.0 ( 0.15 kcal mol-1) definitely lower
than that (7.9 kcal mol-1) measured in 1, in agreement
with the above theoretical predictions. This supports the
existence of the mentioned cogwheel pathway and also
agrees with the predicted arrangement of the phenyl in
position 1, which implies a lower hindrance to the
rotation of the other two phenyl groups with respect to
the case of a methyl bonded to C1. Although this result
provides an indirect support to the computed conforma-
tion of 2, direct evidence, such as that provided by the
X-ray structure, would be desirable.
In the case of 2 we were unable to grow single crystals
suitable for X-ray diffraction, but they could be obtained
for the analogous compound 3, which only differs from 2
by the presence of methoxy groups in the para positions.
As shown in Figure 3, the experimental and computed
structures are quite similar: in particular X-ray diffrac-
tion (see the Supporting Information) confirms that the
plane of the phenyl group bonded to C1 is essentially
orthogonal to the plane identified by C1,C7,C4 in the
norbornane ring.
We also verified that in the case of 3 the barrier for
the rotation of the phenyl in position 1 is NMR invisible
and that the barrier for the observable rotation of the
p-anisyl moieties (∆Gq ) 6.0 ( 0.15 kcal mol-1) is equal,
within the experimental errors, to that measured in the
case of 2 for the corresponding unsubstituted phenyl
groups. In other words, the presence of a methoxy group
does not appreciably affect the rotation barrier.
To obtain an experimental determination of the dy-
namic process involving the phenyl group bonded to C1
it is thus necessary to desymmetrize the molecule by
rendering the two substituents in position 7 different.
Compounds 4 and 5 fulfill, in principle, this requirement.
F IGURE 4. Temperature dependence of the 13C NMR signals
(100.6 MHz) in CHF2Cl/CHFCl2 of the ortho carbons (indicated
as o and o′) of the phenyl in position 1 of compound 4 (left).
On the right is displayed the computer simulation obtained
with the rate constants indicated.
The low-temperature 13C spectra of 4 (Figure 4) actually
show that the ortho carbon signal of the phenyl in
position 1 (identified via HSQC and HMBC sequences10)
splits below -147 °C, indicating that the two ortho
positions are now diastereotopic: the corresponding
rotation barrier was found to be 6.05 ( 0.15 kcal mol-1
.
As in the case of 2 and 3, the ortho signals of the two
aryl substituents in position 7 also split at low temper-
ature in compound 4, and barriers of 6.15 and 6.1 kcal
(12) The computed6 barrier for such
process was found as small as 1.4 kcal mol-1
a
low amplitude libration
.
J . Org. Chem, Vol. 69, No. 2, 2004 347

Casarini et al.
SCHEME 1a
stituent, which was quite broad at ambient temperature,
sharpened on warming as well as on cooling (see the
Supporting Information): such behavior is typical for an
exchange process between two very biased species.14-16
Whereas above ambient temperature the relative inten-
sity of the integrated OMe signal of the o-anisyl sub-
stituent corresponds exactly to three hydrogens, at a
temperature (e.g. -20 °C) where the exchange process
is blocked, its relative intensity is slightly lower. This is
because the observed o-anisyl OMe signal corresponds,
in these conditions, solely to the major of the two
conformers, and lacks the contribution of the minor one.
On this basis we carefully searched for the minor signal,
which was eventually found 0.75 ppm upfield with
respect to its major partner in CDCl3,17 its proportion
being about 5 ( 1% at -20 °C (the minor signals of some
other aliphatic hydrogens also displayed the same pro-
portion).
a
The computed relative energies are in kcal mol-1
.
SCHEME 2
The maximum incremental line-width broadening (∆ω)
measured at 600 MHz for the exchanging ortho OMe line
of 5 was 38 Hz in CDCl3 (at +29 °C) and 27 Hz in toluene-
d8 (at +25 °C). The appropriate formula (k ) 2π∆ω)15
provided the rate constants (k ) 240 and 170 s-1
,
respectively) for the interconversion of the major into the
minor conformer: the barriers (∆Gq) obtained from these
rates turned out to have the same value (14.4 kcal mol-1
in both solvents (Table 1).18
)
mol-1 were determined for the rotation of the phenyl and
of the p-anisyl groups, respectively. These three values
are equal within the experimental uncertainty (see Table
1), in agreement with the proposed correlated process
(cogwheel pathway8) that entails, as mentioned, a com-
mon transition state and, consequently, a unique ∆Gq
value.13
To decide whether the less-hindered E-conformer is
actually more stable than the Z-conformer, a NOE
experiment (DPFGSE-NOE sequence19) was carried out
in toluene-d8 at -20 °C, i.e., a temperature where the
rotation rate is slow in the NMR time scale, thus
minimizing the saturation transfer effects.20 Irradiation
of the CH triplet signal in position 4 of the norbornane
As in the case of 1, the MM computations carried out
on 4 indicate that the rotation of each aryl group drives
the rotation of the other two. This process leads to the
corresponding topomer (where the positions a, c, e are
exchanged, respectively, with the positions b, d, f)
through a unique transition state, shared by the three
rotating aryl groups, as shown in Scheme 1. The com-
puted barrier for this topomerization process (5.6 kcal
mol-1) matches satisfactorily the corresponding experi-
mental value (about 6.1 kcal mol-1) reported in Table 1.
In the case of 5, the restricted rotation about the
o-anisyl to C7 bond is expected to generate two conform-
ers, having the corresponding methoxy group on the same
or on the opposite side with respect to the phenyl bonded
to C1 (Z- and E-conformers, respectively, as in Scheme
2).
(14) (a) Anet, F. A. L.; Basus, V. J . J . Magn. Reson. 1978, 32, 339.
(b) Okazawa, N.; Sorensen, T. S. Can. J . Chem. 1978, 56, 2737.
(15) Sandstro¨m, J . Dynamic NMR Spectroscopy; Academic Press:
New York, 1982; p 84.
(16) Anet, F. A. L.; Yavari, I.; Ferguson, I. J .; Katritzky, A. R.;
Moreno-Man˜as, M.; Robinson, M. I. T. Chem. Commun. 1976, 399.
Cerioni, G.; Piras, P.; Marongiu, G.; Macciantelli, D.; Lunazzi, L. J .
Chem. Soc., Perkin Trans. 2 1981, 1449. Lunazzi, L.; Placucci, G.;
Chatgilialoglu, C.; Macciantelli, D. J . Chem. Soc., Perkin Trans. 2 1984,
819. Casarini, D.; Lunazzi, L.; Macciantelli, D. J . Chem. Soc., Perkin
Trans.
2 1985, 1839. Lunazzi, L.; Placucci, G.; Macciantelli, D.
Tetrahedron 1991, 47, 6427. Lunazzi, L.; Mazzanti, A.; Casarini, D.;
De Lucchi, O.; Fabris, F. J . Org. Chem. 2000, 65, 883. Grilli, S.;
Lunazzi, L.; Mazzanti, A. J . Org. Chem. 2000, 65, 3563.
(17) Such a large upfield shift is due to the fact that the OMe
hydrogens of the o-anisyl in the minor Z-conformer lie almost exactly
above the π-electron system of the p-anisyl ring, a feature that is well-
known to move the corresponding signal upfield (see for instance:
J ackman, L. M.; Sternhell, S. Applications of NMR Spectroscopy to
Organic Chemistry, 2nd ed.; Pergamon Press: Oxford, UK, 1969; p
97. Abraham, R. J .; Fisher, J .; Loftus, P. Introduction to NMR
Spectroscopy; J . Wiley and Sons: Chichester, UK, 1988; p 20. Wu¨thrich,
K. Angew. Chem., Int. Ed. 2003, 42, 3340).
(18) At the temperature (+29 °C) where the maximum broadening
of the major OMe signal occurs in CDCl3, the proportion of the minor
conformer should be about 8%, according to the Boltzmann equation.
By making use of this value and of the measured chemical shifts
separation (i.e. 450 Hz, corresponding to 0.75 ppm at 600 MHz), a
computer line shape simulation did reproduce the experimental
broadening (38 Hz) when the same rate constant (240 s-1), previously
derived from the approximate formula, was employed. This provides
an independent check of the 14.4 kcal mol-1 value for the intercon-
version barrier.
The 1H NMR spectrum of 5, in both CDCl3 and toluene-
d8, showed that the methoxy line of the o-anisyl sub-
(13) As pointed out by one of the reviewers, even more important
for assessing a correlated rotation is the near identity of the rate
constants at the very same temperature (in such a way that the errors
on the measure of temperature do not interfere with the result). In
the spectra of 4 we could simulate the line shape, resulting from the
three simultaneous rotation processes at a common temperature, in
three cases (due to the different chemical shifts separation, the effects
of the three motions were not simultaneously measurable in the whole
temperature range). The rate constants for the three processes were
found exactly equal to each other at -149 and -147 °C (40 and 70
s-1, respectively): at -141 °C their differences were also very similar
and, in any case, smaller than the uncertainty (about (15%) on the
rate obtained from the simulation (the three values were, in fact, 160,
180, and 190 s-1, for the phenyl-C7, p-anisyl-C7, and phenyl-C1
rotation, respectively). These observations thus support the existence
of a correlated motion.
(19) Stonehouse, J .; Adell, P.; Keeler, J .; Shaka, A. J . J . Am. Chem.
Soc. 1994, 116, 6037. Stott, K.; Stonehouse, J .; Keeler, J .; Hwang, T.
L.; Shaka, A. J . J . Am. Chem. Soc. 1995, 117, 4199. Stott, K.; Keeler,
J .; Van, Q. N.; Shaka, A. J . J . Magn. Reson. 1997, 125, 302. Van, Q.
N.; Smith, E. M.; Shaka, A. J . J . Magn. Reson. 1999, 141, 191.
348 J . Org. Chem., Vol. 69, No. 2, 2004

Conformational Studies by Dynamic NMR
SCHEME 3
environment,22 into a pair of equally intense peaks
(separated by 1.0 Hz at 600 MHz, as shown in the
Supporting Information) corresponding to the signals
expected for the two possible enantiomers. In fact,
although compound 4 apparently has three asymmetric
carbons (i.e. carbons in positions 1, 4, and 7 of the
norbornane moiety), only a pair of enantiomers can
exist: a change in the chirality of C7 implies, in fact, a
simultaneous change of the configuration of the other two
stereogenic centers (C1 and C4) that cannot therefore
display a configuration independent of that of carbon in
position 7.23
By making use of an appropriate enantioselective
column (see the Experimental Section) two well-resolved
peaks were actually detected in the HPLC chromatogram
of 4, as shown in Figure 5, where the corresponding
oppositely phased CD spectra are also reported.
F IGURE 5. Enantioselective HPLC chromatogram (top) and
CD spectra (bottom) of the enantiomers of 4, the bold trace
being that of the first eluted enantiomer. The terms R and S
refer to the configuration of carbon in position 7 of the
norbonane ring.
ring of the major conformer results in an enhancement
of the corresponding major OMe line of the o-anisyl
substituent and, likewise, irradiation of the latter line
enhances the triplet of CH in position 4 (see the Sup-
porting Information). Since the computed6 average dis-
tance between the CH in position 4 and the OMe
hydrogens of the o-anisyl group is 6.8 Å in the Z- and
3.9 Å in the E-conformer, the observed NOE effect clearly
establishes that compound 5 essentially adopts the E
conformation.
Exp er im en ta l Section
Ma ter ia l. Compounds 1-4 were obtained according to the
general procedure reported in Scheme 3.
Restricted rotation was also observed for the aryl
groups bonded to C1 and C7, which displayed aniso-
chronous 13C lines at -145 °C (see the Supporting
Information) for the corresponding ortho and meta
carbons (assigned by COSY and HSQC sequences10).
Computer line shape analysis provided ∆Gq values of 7.5
and 6.7 kcal mol-1 for the phenyl-C1 and for the p-anisyl-
C7 bond rotation, respectively (Table 1). Contrary to the
case of 4, the barriers for the three rotating aryl groups
of 5 have different values. This indicates that the
presence of the bulky o-anisyl substituent has disrupted
the correlated rotation process occurring in 4 and has
made each aryl group of 5 rotate independently of the
other. For this reason we found three different activation
energies (see Table 1) that correspond to the three
possible transition states.21
All reactions were carried out under a nitrogen atmosphere,
diethyl ether was dried over Na/benzophenone and CH2Cl2
over P2O5, benzene and anisole were dried by stirring overnight
with activated molecular sieves (4Å, 4-8 mesh) under nitrogen
atmosphere.
Compounds 6a , 7a , and 8a were prepared according to the
procedure described in the literature,24 but in the last step only
3 equiv of PCC (pyridinium chlorochromate) was used.
2-P h en ylbicyclo[3.2.0]h ep ta n -2-ol (6b). 6b was obtained
as previously reported24 starting from bicyclo[3.2.0]heptan-2-
one and PhMgBr. Pale yellow oil, yield 98%. 1H NMR (200
MHz, CDCl3, 25 °C): δ 1.39-1.72 (m, 3 H), 1.86-2.53 (m, 5 H
(21) The barriers for the phenyl-C1 and for the p-anisyl-C7 bond
rotation in 5 are higher than the corresponding barriers measured in
4 (Table 1). This further supports the existence of a correlated motion
in 4 and its absence in 5. Correlated processes are known, in fact, to
reduce the barriers that make the rotation pathways more facile.1c,8
(22) Use was made of a 75:1 molar excess of enantiopure TFA, i.e.,
R-l-1-(9-anthryl)-2,2,2,-trifluoroethanol (see: Pirkle, W. H. J . Am.
Chem. Soc. 1966, 88, 1837) in a CD2Cl2 solution at about -17 °C.
(23) If C7 has the R configuration, C1 and C4 have, forcibly, the S
and R configuration, respectively. Likewise, if C7 has the S configu-
ration, C1 and C4 must be R and S, respectively.
As mentioned, compound 4 does not possess any
element of symmetry (C1 point group): the 1H NMR
single line of the methoxyl group thus splits, in a chiral
(20) Neuhaus, D.; Williamson, M. P. The Nuclear Overhauser Effect
in Structural and Conformational Analysis; VCH: New York, 1989;
Chapter 5.
(24) Kirmse, W.; Steru, J . Synthesis 1983, 994.
J . Org. Chem, Vol. 69, No. 2, 2004 349

Casarini et al.
+ OH), 2.73-3.00 (m, 2 H), 7.16-7.38 (m, 5 H, Ph). 13C NMR
(50.3 MHz, CDCl3, 25 °C): δ 18.2 (CH2), 24.5 (CH2), 30.2 (CH2),
38.0 (CH), 39.0 (CH2), 46.4 (CH), 83.0 (Cq), 125.2 (CH), 126.7
(CH), 128.0 (CH), 148.0 (Cq).
1-P h en yl-7-(4-m eth oxyp h en yl)bicyclo[2.2.1]h ep ta n -7-
ol (10). Sticky solid (75%). 1H NMR (400 MHz, CDCl3, 25 °C):
δ 1.34-1.42 (m, 1 H, CH2), 1.49-1.66 (m, 2 H, CH2), 1.74-
1.84 (m, 2 H, CH2), 1.99-2.07 (m, 1 H, CH2), 2.27-2.36 (m, 1
H, CH2), 2.44-2.51 (m, 1 H, CH2), 2.61 (br t, J ) 4.4 Hz, 1 H,
CH), 3.71 (s, 3 H, OCH3), 6.65-6.68 (m, 2 H, anisole), 7.02-
7.06 (m, 2 H, anisole), 7.24-7.29 (m, 1 H, Ph), 7.32-7.37 (m,
2 H, Ph), 7.62-7.65 (m, 2 H, Ph). 13C NMR (100.6 MHz, CDCl3,
25 °C): δ 25.8 (CH2), 28.2 (CH2), 31.5 (CH2), 40.6 (CH2), 46.7
(CH), 52.6 (Cq), 55.1 (OCH3), 88.0 (Cq), 113.4 (CH), 126.1 (CH),
127.5 (CH), 128.1 (CH), 128.5 (CH), 134.5 (Cq), 144.0 (Cq), 158.6
(Cq).
Compounds 1, 2, 3, and 4 were prepared from the corre-
sponding alcohols in accordance with a general procedure.25
A solution of 9a , 9b, or 10 (1 mmol) in 5 mL of benzene (1 and
2) or anisole (3 and 4) was slowly added under nitrogen into
a flask containing trifluoromethanesulfonic acid (1.5 mmol) in
5 mL of the same solvent. After being stirred for 1.5 h, the
mixture was poured into water (20 mL) and the aqueous
solution was neutralized with solid NaHCO3 and extracted
with CH2Cl2 (20 mL). The organic layer was dried (Na2SO4)
and the solvent removed at reduced pressure. A further
purification of the products was obtained by silica gel chro-
matography (1, petroleum ether, 3, petroleum ether/Et2O 10:
1, 4, cyclohexane/toluene 20:1), or by recrystallization (ethanol,
2).
1-P h en ylbicyclo[2.2.1]h ep ta n -7-ol (7b). To a concen-
trated sulfuric acid solution in acetic acid (0.5 N, 42 mL) was
added 6b (5.88 g, 31.3 mmol). The mixture was stirred for 5 h
at 80 °C, neutralized with NaHCO3, and partitioned between
water (400 mL) and Et2O (150 mL). After being stirred for 10
min, the organic layer was separated, dried (sodium sulfate),
filtered on silica gel, and concentrated. The residue was
dissolved in dry Et2O (70 mL) and slowly added to a solution
of LiAlH4 (2.04 g, 53.8 mmol) in dry Et2O (30 mL) at 0 °C.
The reaction was stirred for 2 h at ambient temperature,
quenched (saturated ammonium chloride solution), and filtered
on Celite. The mixture was then extracted with Et2O and dried
(Na2SO4) and the solvent was removed at reduced pressure
affording a brown oil (5.09 g). The crude was purified by silica
gel chromatography (petroleum ether/Et2O 7:3) to yield 3.44
g (18.3 mmol) of 7b as a yellow solid (60%). 1H NMR (400 MHz,
CDCl3, 25 °C): δ 1.31-1.38 (m, 1 H), 1.49-1.83 (m, 5 H +
OH), 2.10-2.17 (m, 2 H), 2.19-2.22 (m, 1 H), 4.23 (br s, 1 H),
7.08-7.15 (m, 1 H), 7.30-7.37 (m, 4 H). 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ 25.9 (CH2), 28.0 (CH2), 31.5 (CH2), 36.8 (CH2),
41.3 (CH), 53.2 (Cq), 81.7 (CH), 126.1 (CH), 127.0 (CH), 128.4
(CH), 143.3 (Cq).
1-Met h yl-7,7-d ip h en ylb icyclo[2.2.1]h ep t a n e (1). Solid
(53%); mp 73-73.5 °C. H NMR (300 MHz, CDCl3, 25 °C): δ
1-P h en ylbicyclo[2.2.1]h ep ta n -7-on e (8b). To a solution
of 7b (3.44 g, 18.3 mmol) in dry CH2Cl2 (60 mL) were added
molecular sieves (4Å, activated powder, 10 g) and PCC (5.9 g,
27.4 mmol). After being stirred at ambient temperature for 1
h, the mixture was diluted with dry Et2O (100 mL) and stirred
for an additional 1 h. The brown suspension was filtered on
Celite and subsequently on silica gel to give an orange organic
solution that was concentrated under reduced pressure. The
byproduct contained in the crude (1-phenyl-2-oxabicyclo[2.2.2]-
octan-3-one) was eliminated by precipitation from Et2O.
Product 8b was obtained as a pale yellow oil (1.85 g, 9.95
mmol) and used for the next steps without further purification.
1H NMR (400 MHz, CDCl3, 25 °C): δ 1.69-1.76 (m, 2 H), 2.00-
2.21 (m, 7 H), 7.23-7.36 (m, 5 H). 13C NMR (100.6 MHz,
CDCl3, 25 °C): δ 23.8 (CH2), 31.8 (CH2), 40.4 (CH), 47.8 (Cq),
126.4 (CH), 127.6 (CH), 128.1 (CH), 138.8 (Cq), 214.9 (Cq).
The alcohols 9a , 9b, and 10 were synthesized according to
the following general procedure. Four millimoles of the ketone
(8a , 8b ) dissolved in dry Et2O (5 mL) was slowly added at
ambient temperature to a solution of the appropriate Grignard
reagent (6 mmol of phenyl- or 4-methoxyphenylmagnesium
bromide). The mixture was refluxed for about 1 h then
quenched with saturated ammonium chloride solution, ex-
tracted with Et2O, dried (Na2SO4), and concentrated at reduced
pressure. The residue was purified by silica gel chromatogra-
phy (petroleum ether/Et2O 5:1, 9a , or petroleum ether/Et2O
10:1, 9b). The crude alcohol 10 was directly used in the
following step.
1
1.26-1.41 (m, 4 H, CH2), 1.58-1.78 (m, 4 H, CH2), 1.65 (s, 3
H, CH3), 2.98 (br t, J ) 4.0 Hz, 1 H, CH), 7.01-7.07 (m, 2 H,
Ph), 7.13-7.20 (m, 4 H, Ph), 7.42-7.46 (m, 4 H, Ph). 13C NMR
(75.45 MHz, CDCl3, 25 °C): δ 20.1 (CH3), 27.6 (CH2), 38.0
(CH2), 46.2 (CH), 48.5 (Cq), 62.5 (Cq), 125.1 (CH, para), 127.8
(CH, meta), 127.9 (CH, ortho), 146.0 (Cq). Anal. Calcd for
C
20H22: C (91.55); H (8.45). Found: C (91.53); H (8.42).
1,7,7-Tr ip h en ylbicyclo[2.2.1]h ep ta n e (2). Solid (65%);
mp 133.5-134 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ 1.46-
1.51 (m, 2 H, CH2), 1.67-1.72 (m, 2 H, CH2), 2.04-2.09 (m, 2
H, CH2), 2.39-2.44 (m, 2 H, CH2), 3.33 (t, J ) 4.3 Hz, 1 H,
CH), 7.01-7.04 (m, 2 H, Ph), 7.09-7.12 (m, 4 H, Ph), 7.27-
7.30 (m, 3 H Ph), 7.32-7.35 (m, 2 H, Ph), 7.48-7.50 (m, 2 H,
Ph). 13C NMR (100.6 MHz, CDCl3, 25 °C): δ 28.1 (CH2), 36.8
(CH2), 46.3 (CH), 55.0 (Cq), 64.6 (Cq), 125.3 (CH, para), 126.2
(CH, para), 127.4 (CH, meta), 127.5 (CH, meta), 128.9 (CH,
ortho), 130.1 (CH, ortho), 142.8 (Cq), 145.4 (Cq). Anal. Calcd
for C25H24: C (92.54); H (7.46). Found: C (91.53); H (7.45).
7,7-B is (4-m e t h o x y p h e n y l)-1-p h e n y lb ic y c lo [2.2.1]-
h ep ta n e (3). Solid (50%); mp 162-163 °C. 1H NMR (400 MHz,
CDCl3, 25 °C): δ 1.43-1.51 (m, 2 H, CH2), 1.65-1.72 (m, 2 H,
CH2), 2.00-2.09 (m, 2 H, CH2), 2.35-2.43 (m, 2 H, CH2), 3.24
(bt, J ) 4.3 Hz, 1 H, CH), 3.70 (s, 6 H, OCH3), 6.63-6.67 (m,
4 H, anisole), 7.15-7.19 (m, 4 H, anisole), 7.25-7.30 (m, 1 H,
Ph), 7.31-7.36 (m, 2 H, Ph), 7.47-7.50 (m, 2 H, Ph). 13C NMR
(100.6 MHz, CDCl3, 25 °C): δ 28.2 (CH2), 36.8 (CH2), 46.6 (CH),
55.0 (OCH3), 55.1 (Cq), 63.3 (Cq), 112.8 (CH, ortho, anisole),
126.1 (CH, para, Ph), 127.4 (CH, meta, Ph), 129.8 (CH, meta,
anisole), 130.0 (CH, ortho, Ph), 138.0 (Cq), 143.0 (Cq), 156.9
(Cq). Anal. Calcd for C27H28O2: C (84.34), H (7.34). Found: C
(84.36); H (7.36).
1-Meth yl-7-p h en ylbicyclo[2.2.1]h ep ta n -7-ol (9a ). Solid
1
(45%). H NMR (300 MHz, CDCl3, 25 °C): δ 1.26-1.41 (m, 4
H, CH2), 1.58-1.78 (m, 4 H, CH2), 1.65 (s, 3 H, CH3), 2.98 (br
t, J ) 4.0 Hz, 1 H, CH), 7.01-7.07 (m, 2 H, Ph), 7.13-7.20
(m, 4 H, Ph), 7.42-7.46 (m, 4 H, Ph). 13C NMR (75.45 MHz,
CDCl3, 25 °C): δ 20.1 (CH3), 27.6 (CH2), 38.0 (CH2), 46.2 (CH),
48.5 (Cq), 62.5 (Cq), 125.1 (CH), 127.8 (CH), 127.9 (CH), 146.0
(Cq).
7-(4-Me t h o x y p h e n y l)-1,7-d i p h e n y lb i c y c lo [2.2.1]-
h ep ta n e (4). Solid (90%); mp 134-135 °C. 1H NMR (600 MHz,
CDCl3, 25 °C): δ 1.45-1.51 (m, 2 H, CH2), 1.66-1.72 (m, 2 H,
CH2), 1.98-2.04 (m, 1 H, CH2), 2.08-2.14 (m, 1 H, CH2), 2.35-
2.46 (m, 2 H, CH2), 3.29 (bt, J ) 4.3 Hz, 1 H, CH), 3.71 (s, 3
H, OCH3), 6.65-6.67 (m, 2 H, anisole), 7.00-7.04 (m, 1 H, Ph),
7.08-7.12 (m, 2 H, Ph), 7.18-7.21 (m, 2 H, anisole), 7.25-
7.30 (m, 3 H, Ph), 7.32-7.35 (m, 2 H, Ph), 7.48-7.50 (m, 2 H,
Ph). 13C NMR (150.8 MHz, CDCl3, 25 °C): δ 28.1 (CH2), 28.2
(CH2), 36.4 (CH2), 37.2 (CH2), 46.4 (CH), 55.0 (OCH3), 55.1 (Cq),
1,7-Dip h en ylbicyclo[2.2.1]h ep ta n -7-ol (9b). Sticky solid
1
(50%). H NMR (400 MHz, CDCl3, 25 °C): δ 1.36-1.43 (m, 1
H, CH2), 1.51-1.66 (m, 2 H, CH2), 1.75-1.85 (m, 2 H, CH2),
1.88 (s, 1 H, OH), 2.01-2.10 (m, 1 H, CH2), 2.30-2.38 (m, 1
H, CH2), 2.45-2.53 (m, 1 H, CH2), 2.65 (bt, J ) 4.4 Hz, 1 H,
CH), 7.12-7.17 (m, 5 H, Ph), 7.26-7.30 (m, 1 H, Ph), 7.32-
7.37 (m, 2 H, Ph), 7.62-7.65 (m, 2 H, Ph). 13C NMR (75.45
MHz, CDCl3, 25 °C): δ 25.8 (CH2), 28.1 (CH2), 31.5 (CH2), 40.6
(CH2), 46.6 (CH), 52.6 (Cq), 88.4 (Cq), 126.1 (CH), 127.3 (CH),
127.4 (CH), 127.5 (CH), 128.2 (CH), 142.2 (Cq), 143.9 (Cq).
(25) Martinez, A. G.; Barcina, J . O.; Cerezo, A. F.; Schlu¨ter, A.-D.;
Frahn, J . Adv. Mater. 1999, 11, 27.
350 J . Org. Chem., Vol. 69, No. 2, 2004

Conformational Studies by Dynamic NMR
64.0 (Cq), 112.8 (CH, ortho, anisole), 125.1 (CH, para, Ph),
126.2 (CH, para, Ph), 127.4 (CH, meta, Ph), 127.5 (CH, meta,
Ph), 128.7 (CH, ortho, Ph), 130.0 (CH, meta, anisole), 130.1
(CH, ortho, Ph), 137.5 (Cq), 142.9 (Cq), 146.0 (Cq), 157.0 (Cq).
Anal. Calcd for C26H26O: C (88.09); H (7.39). Found: C (88.11);
H (7.36).
7-(2-Met h oxyp h en yl)-7-(4-m et h oxyp h en yl)-1-p h en yl-
bicyclo[2.2.1]h ep ta n e (5). To a solution of mesityllithium
(1.24 mmol) in dry THF (3 mL) cooled to -78 °C was added
ketone 8b (210.mg, 1.13 mmol). The mixture was warmed to
ambient temperature, further stirred for 1 h, quenched with
introduced into the precooled probe of the spectrometer. The
temperatures were calibrated by substituting the sample with
a precision Cu/Ni thermocouple before the measurements.
Complete fitting of the dynamic NMR line shape was carried
out by using a PC version of the DNMR-6 program.26
HP LC sep a r a tion of the enantiomers of 4 was performed
at +25 °C on a Chiralcel OD-H column (5 µm), 250 mm × 4.6
mm ID, UV 254 nm, flow rate 0.5 mL/min (n-hexane/iPrOH
99.5:0.5). The necessary amount of the two separated enan-
tiomers was obtained by collecting several elutions.
CD spectra of the enantiomers of 4 were recorded at +25
°C on a J asco J -600 dicrograph in a 0.01 cm cell in the range
185-325 nm.
a
saturated NH4Cl solution, extracted with Et2O, dried
(Na2SO4), and concentrated at reduced pressure. Purification
by silica gel chromatography (petroleum ether/Et2O 9:1)
provided the alcohol 7-mesityl-1-phenylbicyclo[2.2.1]heptan-
7-ol as a white solid (170 mg, 0.56 mmol, 49%). Under the same
conditions reported above,25 the reaction with trifluoromethane-
sulfonic acid (0.78 mmol) in anisole (3 mL) supplied a mixture
of 3 and 5 that were separated by preparative TLC (petroleum
ether/Et2O 10:1) to yield 46 mg (0.12 mmol, 23%) and 50 mg
(0.13 mmol, 25%), respectively. Mp of 5 177.5-178.0 °C
(ethanol). 1H NMR (300 MHz, CDCl3, 25 °C): δ 1.32-1.58 (m,
4 H, CH2), 1.71-1.81 (m, 1 H, CH2), 1.97 (br s, 1 H, CH2), 2.41
(br s, 1 H, CH2), 2.81 (br s, 1 H, CH2), 3.40 (br s, 3 H, OCH3),
3.71-3.78 (m, 1 H, CH), 3.75 (s, 3 H, OCH3), 6.62-6.69 (m, 4
H, Ar), 7.00-7.07 (m, 1 H, Ar), 7.17-7.32 (m, 5 H, Ar), 7.39-
7.43 (m, 2 H, Ar), 7.52-7.57 (m, 1 H, Ar). 13C NMR (75.45
MHz, CDCl3, 25 °C): δ 28.2 (CH2), 29.3 (CH2), 33.5 (br s, CH2),
40.8 (br s, CH2), 45.2 (br s, CH), 55.0 (OCH3), 55.3 (br s, OCH3),
55.6 (Cq), 63.1 (Cq), 111.5 (CH), 112.4 (CH), 119.6 (CH), 125.7
(CH), 126.8 (CH), 127.3 (CH), 128.1 (CH), 129.8 (CH), 132.0
(CH), 143.8 (Cq), 157.0 (Cq), 157.5 (Cq), Anal. Calcd for
Ack n ow led gm en t. This work is dedicated to Pro-
fessors Bianca F. Bonini and Binne Zwanenburg on the
occasion of their 70th birthday. Thanks are due to Prof.
F. Cozzi, University of Milan, for reading the manu-
script and providing helpful comments. Financial sup-
port from the University of Bologna (Funds for selected
research topics 2001-2002 and RFO) and from MIUR-
COFIN 2001, Rome (national project Stereoselection in
Organic Synthesis), was received by L.L. and A.M.
Support from the University of Basilicata and from
MIUR-COFIN 2001, Rome (New theoretical and experi-
mental methods for the assignment of the molecular
configuration in solution), was also received by D.C.
Su p p or tin g In for m a tion Ava ila ble: MMX data for 1-5;
crystallographic data and ORTEP drawing of 3; temperature
1
1
dependence of the OMe H signals of 5; NOE spectra of 5; H
spectrum of 4 in chiral medium; temperature dependence of
13C aromatic signals of 5. This material is available free of
charge via the Internet at http://pubs.acs.org.
C
27H28O2: C (84.34); H (7.34). Found: C (84.31); H (7.33).
NMR Sp ectr a . The samples for the low-temperature meas-
urements were prepared by connecting to a vacuum line the
NMR tubes containing the compound and some deuterated
solvent for locking purposes and condensing therein the
gaseous solvents (CHF2Cl and CHFCl2) by means of liquid
nitrogen. The tubes were subsequently sealed in vacuo and
J O035411N
(26) QCPE program no. 633, Indiana University, Bloomington, IN.
J . Org. Chem, Vol. 69, No. 2, 2004 351