Conformational studies by dynamic NMR. 84.1 Structure, conformation, and stereodynamics of the atropisomers of N-aryl-tetrahydropyrimidines

Article abstract of DOI:10.1021/jo015743x

The existence of stereolabile atropisomers for a number of N-aryl-tetrahydropyrimidines in solution has been deduced from the observation of the anisochronous NMR signals of prochiral methylene groups. The interconversion barriers for these atropisomers h

Full text of DOI:10.1021/jo015743x

J . Org. Chem. 2001, 66, 6679-6684
6679
Con for m a tion a l Stu d ies by Dyn a m ic NMR. 84.1 Str u ctu r e,
Con for m a tion , a n d Ster eod yn a m ics of th e Atr op isom er s of
N-Ar yl-tetr a h yd r op yr im id in es
Ma. Beatriz Garcia,2 Stefano Grilli, Lodovico Lunazzi,* Andrea Mazzanti, and
Liliana R. Orelli2,*
Department of Organic Chemistry “A.Mangini”, University of Bologna,
Viale Risorgimento, 4, Bologna 40136, Italy
lunazzi@ms.fci.unibo.it
Received May 10, 2001
The existence of stereolabile atropisomers for a number of N-aryl-tetrahydropyrimidines in solution
has been deduced from the observation of the anisochronous NMR signals of prochiral methylene
groups. The interconversion barriers for these atropisomers have been measured by line shape
analysis of dynamic NMR spectra at various temperatures: a Molecular Mechanics modeling
resulted in good agreement with these values. In an appropriate case, distinct NMR signals for
the two enantiomeric forms could be observed at ambient temperature in a chiral environment.
Evidence was also obtained for an exchange process occurring between two conformers experiencing
a very biased equilibrium. Single-crystal X-ray diffraction of one such compound yielded a molecular
structure in good agreement with the results obtained by ab initio calculations.
In tr od u ction
Resu lts a n d Discu ssion
Diversely substituted tetrahydropyrimidines have in-
teresting biological activity3-5 and pharmacological prop-
erties, acting as anthelmintics,6 antidepressants,7 and
fungicides,8 among others. In this context a number of
yet unknown N-aryl-substituted tetrahydropyrimidines
have been prepared, and the related stereochemical
properties investigated here.
Ab initio calculations (RHF 3-21G* method9) applied
to the o-chloro derivative 1 indicate indeed that the C2′-
C1′-N1-C6 dihedral angle has a value of 72°, thus
entailing the existence of two enantiomeric forms: in
Figure 1 the computed structures predicted for this pair
of enantiomers are displayed. A single-crystal X-ray
diffraction of 1 confirms the theoretical results, in that
shows that two of the four molecules within the crystal
cell are the antipodes of the other two. The geometrical
parameters determined in the solid state are quite
similar to those computed for the isolated molecule, in
particular the mentioned dihedral angle has a very
similar value (71.1°). The experimental X-ray structures
of the antipodes of 1 are also displayed in Figure 1.
In particular, hindered N-aryl-tetrahydropyrimidines
such as 1-3 are expected to have the plane of the ortho-
substituted phenyl ring significantly twisted with respect
to the time-averaged dynamic plane of the six-membered
pyrimidine ring. The existence of such an Ar-N stereo-
genic axis would originate, in principle, a pair of stereo-
labile enantiomeric forms (atropisomers) if the corre-
sponding rotation rate is rendered sufficiently slow.
Whereas in the crystalline state the internal molecular
motions are frozen, so that the mentioned atropisomers
can be regarded as stable species, this is not the case in
solution where the internal motions happen to be quite
rapid. For this reason the existence of the atropisomers
of 1 in solution can be inferred by investigating the NMR
spectra at a temperature sufficiently low as to make the
rate of the enantiomerization process, brought about by
the rotation about the Ar-N stereogenic axis, negligible.
Although the NMR spectra of a pair of enantiomers are
indistinguishable, the presence of prochiral probes allows
one to detect the asymmetry of the molecule.10 In the
present case the two hydrogens of each methylene moiety
(1) Part 82. Casarini, D.; Lunazzi, L.; Mazzanti, A. Angew. Chem.,
Int. Ed. 2001, 40, 2536. Part 83. Grilli, S.; Lunazzi, L.; Mazzanti, A.
J . Org. Chem. 2001, in press (Ms. J O010420m).
(2) On leave of absence from the Departamento de Quimica Or-
ganica, Facultad de Farmacia y Bioquimica, Universidad de Buenos
Aires, J unin 956, Buenos Aires, 1113 Argentina (e-mail: lorelli@
ffyb.uba.ar).
(7) Weinhardt, K.; Wallach, M B.; March, M. J . Med. Chem. 1985,
28, 694.
(3) Dunbar, P. G.; Durant, G. J .; Fang, Z. J . Med. Chem. 1993, 36,
842.
(4) Dunbar, P. G.; Durant, G. J .; Rho, T. J . Med. Chem. 1994, 37,
2774.
(8) (a) Carter, P. A.; Pfrengle, W. F. UK Patent Appl. GB 2,277,089
(1994). Chem. Abstr. 1994, 122, 31544a. (b) Carter, P. A.; Pfrengle, W.
F. UK Patent Appl. GB 2,277,090 (1994). Chem. Abstr. 1994, 122,
31544b.
(5) Bernard, T.; J ebbar, M.; Rassouli, Y.; Himdi-Kabbab, S.; Hame-
lin, J .; Blanco, C. J . Gen. Microbiol. 1993, 139, 126.
(6) McFarland, J . W.; Howes, H. L. J . Med. Chem. 1972, 15, 365
and references quoted therein.
(9) Computer package Spartan Pro 1.1
(10) Mislow, K.; Raban, M. Topics Stereochem. 1967, 1, 1. J ennings,
W. B. Chem. Rev. 1975, 75, 307. Eliel, E. L. J . Chem. Educ. 1980, 57,
52.
10.1021/jo015743x CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/11/2001

6680 J . Org. Chem., Vol. 66, No. 20, 2001
Garcia et al.
F igu r e 1. Ab initio computed structures of the atropisomers
of 1 (top). Underneath are reported the experimental struc-
tures as obtained by X-ray diffraction.
F igu r e 2. 300 MHz 1H experimental signals (left) of the CH2
hydrogens of 1 in positions 4 and 6 monitored at various
temperatures in toluene-d8 whereas decoupling at the fre-
quency of CH2 in position 5. On the right are reported the
traces simulated with the rate constants indicated.
are enantiotopic (and the corresponding NMR signals
accordingly isochronous) when the enantiomerization
process, responsible for the time averaged symmetry (Cs
point group), is fast in the NMR time-scale. These
hydrogens become, however, diastereotopic, and the
corresponding signals consequently anisochronous, when
this process becomes sufficiently slow: in these conditions
the molecule appears in fact asymmetric (C1 point group),
thus chiral. To simplify the pattern of the 1H NMR
spectrum in the methylene region, the signals of the CH2
in position 5 of compound 1 were saturated, making the
pairs of hydrogens within the CH2 moieties in positions
4 and 6 to yield each a single line when enantiotopic (e.g.,
at +80 °C, as in Figure 2). On the other hand, when the
spectrum is recorded at lower temperature (e.g., at -9
°C as in Figure 2) these hydrogens appear diastereotopic,
each pair yielding the typical four-line pattern of an AB-
type system. At intermediate temperatures the lines are
broadened by the enantiomerization process which ex-
changes the relative positions of the methylene hydro-
gens, the corresponding rates can be therefore obtained
by computer simulation11 (Figure 2, right).
o-chloro phenyl group in 1, thus confirming that this
motion is responsible for the observed enantiomerization.
In Figure 3 the three-dimensional energy surface, com-
puted as a function of the rotation angles about the Ar-N
and the Ph-C axes (θ and æ, respectively), is displayed:
the full line represents the pathway required for the
interconversion of the stereolabile atropisomers. These
calculations show how the saddle point corresponding to
the rotation transition state of 13.5 kcal mol-1 describes
the situation where the chlorine atom crosses over the
CH2 moiety in position 6. The other possible transition
state, where the chlorine atom crosses over the phenyl-
bonded trigonal carbon in position 2, has an energy 2 kcal
mol-1 higher. Although this computed difference is not
very large and might be due, at least in part, to the
approximations of the theoretical model employed, it does
not seem unreasonable to conclude that the enantiomer-
ization of the atropisomers of 1 is more likely to occur
through the former of these two pathways, due to the
inferior energy of its saddle point.
From these data a free energy of activation of 15.0 kcal
mol-1 is obtained for the interconversion of the stereo-
labile atropisomers of 1.12 This value corresponds satis-
factorily to the barrier of 13.5 kcal mol-1 computed by
Molecular Mechanics13 for the rotation process of the
Analogous results were obtained in the case of 2 (X )
NO2) and 3 (X ) Me), the measured enantiomerization
barriers being lower for the nitro derivative 2 (14.2 kcal
mol-1) and higher for the methyl derivative 3 (16.6 kcal
mol-1). The experimental ∆Gq values (Table 1) follow the
same trend of the effective van der Waals radii of the
substituents, i.e., 1.73, 1.61, and 1.80 Å for the chlorine,
nitro, and methyl groups, respectively.14 This suggests
(11) PC version of the DNMR 6 computer program QCPE 663,
Indiana University, Bloomington, IN.
(12) As often observed in conformational processes, the ∆Gq value
is independent of temperature within the experimental errors, indicat-
ing a negligible value for ∆Sq. See: Lunazzi, L.; Macciantelli, D.; Grossi,
L. Tetrahedron 1983, 39, 305. Anderson, J . E.; Tocher, D. A.; Casarini,
D., Lunazzi, L. J . Org. Chem. 1991, 56, 1731. Borghi, R.; Lunazzi, L.;
Placucci, G.; Cerioni, G.; Foresti, E.; Plumitallo, A. J . Org. Chem. 1997,
62, 4924.
(13) Since an ab initio modeling of the energy surface for a relatively
large molecule like 1 would be quite time-consuming and considerably
expensive, the MMX force field (Computer package PC Model, Serena
Software, Bloomington, IN) was employed for calculating the barriers
corresponding to the interconversion pathways of Figure 3.

Atropisomers of N-Aryl-tetrahydropyrimidines
J . Org. Chem., Vol. 66, No. 20, 2001 6681
F igu r e 4. The 1H methyl signal (300 MHz at ambient
temperature) of compound 3 (top) splits into two (bottom) in
the presence of a chiral solvating agent (see text).
F igu r e 3. Energy surface of derivative 1 computed (Molecular
Mechanics) as a function of the rotation angles θ and æ. The
full line represents the pathway for interconverting the
atropisomers, the dotted line the pathway for the topomeri-
sation process (phenyl ring rotation). The scale of the energy
values is in kcal mol-1
.
Ta ble 1. Exp er im en ta l ∆Gq Va lu es (k ca l m ol-1) for th e
Dyn a m ic P r ocesses Occu r r in g in Com p ou n d s 1-4
compd
enantiomerization
topomerization
ring inversion
1
2
3
4
15.0
14.2
16.6
16.6
6.9
7.6
6.8
-
7.0
7.3
6.7
6.0
that the interconversion rates of the atropisomers of 1-3
mainly depend on the steric hindrance of the ortho
substituents.
In the case of 3 (X ) Me) the enantiomerization barrier
is high enough as to allow the direct detection of the two
enantiomers at ambient temperature. As shown in Figure
4 the single line of the methyl group splits into a pair of
singlets of equal intensity (each of them corresponding
to one of the two enantiomers), when the 1H NMR
spectrum is recorded at ambient temperature in an
environment which has been rendered chiral by addition
of an appropriate amount of an enantiopure chiral
solvating agent.15
F igu r e 5. Left: experimental 13C signals (75.5 MHz in CHF2-
Cl) of the ortho and meta carbons of the unsubstituted phenyl
group of 1 as function of temperature. Right: computer
simulation obtained with the rate constants indicated.
As reported in Figure 3, the rotation of the unsubsti-
tuted phenyl group bonded to C-2 follows a pathway
(dotted line) whose transition state has a computed
energy 10 kcal mol-1 higher than the ground state. This
topomerisation process exchanges the positions of the
ortho and meta carbons in 1, and the value of the
calculated barrier (10 kcal mol-1) suggests that such a
motion should be accessible to an experimental NMR
detection. Actually, the single 13C NMR lines observed
for the ortho and for the meta carbons broaden on cooling
below -100 °C and eventually split into a pair of
signals: this is because the restricted rotation about the
Ph-C bond has rendered diastereotopic the two ortho as
well as the two meta carbons. In Figure 5 three lines,
with a 1:1:2 intensity distribution, are observed at -140
°C due to one of the two ortho being accidentally
coincident with one of the two meta signals. Line shape
simulation allowed a free energy of activation of 6.9 (
0.15 kcal mol-1 to be determined, in reasonable agree-
ment with the computed value.
The spectra of compounds 2 and 3 also display the
effect of the topomerisation process: the corresponding
barriers are reported in Table 1.
Two additional internal motions might also occur in
these derivatives, namely inversion of the formally
sp3-hybridized nitrogen atom and inversion of the six-
membered ring. Although it is impossible to discriminate
between these two possibilities solely on experimental
ground, a number of considerations can be nonetheless
(14) Bott, G.; Field, L. D.; Sternhell, S. J . Am. Chem. Soc. 1980,
102, 5618.
(15) Use was made of R-l-1-(9-anthryl)-2,2,2-trifluoroethanol as in:
Pirkle, W. H. J . Am. Chem. Soc. 1984, 106, 477.

6682 J . Org. Chem., Vol. 66, No. 20, 2001
Garcia et al.
Sch em e 1
taken into account to propose a reasonable hypothesis
about the motion which is more likely to be observed by
NMR spectroscopy.
Both the crystal and computed structures indicate that
in 1 the pyramid of the aryl-bonded sp3 nitrogen atom is
quite flat, the degree of pyramidalization being 5.8° (X-
9
ray) or 8° (ab initio ), i.e., values that are much closer
to the 0° of a planar sp2-hybridized nitrogen atom than
to the 27° of the truly pyramidal sp3 nitrogen of trim-
ethylamine.16 Owing to this situation, the N-inversion
barrier of 1 is presumably too low to be amenable to NMR
observation, and this is confirmed by our ab initio
9
calculations that predict an N-inversion barrier in 1
equal to 2.7 kcal mol-1. It has also to be stressed that
N-inversion processes sufficiently high (i.e. >4 kcal mol-1
)
to be measurable by dynamic NMR spectroscopy have
never been reported for arylamines.17 On the other hand,
ring inversion of six-membered heterocycles, comprising
an endocyclic double bond, have barriers accessible to
NMR detection, since a number of derivatives were
found18 to display free energies of activation in the range
7-11 kcal mol-1. The asymmetry resulting from the
“frozen” inversion of the six-membered ring creates a
second source of chirality, in addition to the mentioned
Ar-N stereogenic axis. As a consequence two stereolabile
diastereoisomers, each entailing a pair of enantiomers,
are expected to occur in these derivatives. The ab initio
computation9 for compound 1 predict that, in addition to
the conformation depicted in Figure 1, the restriction of
the ring inversion process should lead to a second
minimum of energy, corresponding to a minor conformer.
The two conformers were labeled anti (1b), when the CH2
moiety in position 5 is on the opposite side of the chlorine
atom, and syn (1a ) when on the same side (Scheme 1).
The corresponding energy difference was computed9 to
be 1.5 kcal mol-1, thus indicating that the proportion of
the less stable conformer syn-1a should be very small
(about 1%) in the temperature range where the ring
inversion becomes sufficiently slow for NMR observation.
For this reason it is unlikely that the spectrum of the
minor conformer is directly visible.
F igu r e 6. 13C signals (75.5 MHz in CHF2Cl) of the three
methylene carbons of 1 at different temperatures. At -127 °C
the central line broadens more than the other two, but
sharpens again at -147 °C, indicating the occurrence of an
exchange process involving an invisible species (see text).
process between two species experiencing a very biased
equilibrium.19
The relationship k ) 2π∆ω, where ∆ω represents the
20
maximum incremental width (in the case of 1 ∆ω was
found 14 ( 1 Hz at 75.5 MHz), allows one to obtain the
rate constant, hence the ∆Gq value (7.0 ( 0.2 kcal mol-1
)
for the ring inversion process. An estimate of the signal-
to-noise ratio indicates that the amount of the minor
conformer 1a is certainly lower than 10%, in agreement
with the theoretical prediction. As shown in Table 1
similar results were obtained for 2 and 3.
It should be also noticed that in 1-3 the topomeriza-
tion and ring inversion barriers (Table 1) are equal within
the experimental errors. This might be due to an ac-
cidental coincidence, even though the possibility that
these equal values are the consequence of a correlated
motion cannot be, in principle, excluded. If so, the
measured ∆Gq values would be the manifestation of an
unique dynamic process. A definite evidence, however,
is not available to support this hypothesis which remains,
therefore, rather speculative.
Actually, in the low temperature 13C spectrum of 1 the
signals of the minor conformer were not detected, but its
presence could be nonetheless established in an indirect
manner. For it was observed that one CH2 broadens at
low temperature considerably more than the other two
CH2 lines, reaches a maximum width at -127 °C, and
sharpens again on further cooling to -147 °C (Figure 6).
This is the typical feature expected for an exchange
With the purpose of achieving direct evidence for the
presence of two conformers, we searched for a compound
(19) Anet, F. A. L.; Yavari, I.; Ferguson, I. J .; Katritzky. A. R.;
Moreno-Man˜as, M.; Robinson, M. J . T. J . Chem. Soc., 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. Grilli, S.; Lunazzi, L.; Mazzanti, A. J .
Org. Chem. 2000, 65, 3563.
(16) The degree of piramidalization is defined as 360° - Σ RNR,
see: Ganguly, B.; Freed, D. A.; Kozlowski, M. C. J . Org. Chem. 2001,
66, 1103.
(17) (a) Brand, J . C. D.; Williams, D. R.; Cook, T. J . J . Mol. Spectrosc.
1966, 20, 359. (b) Lambert, J . B.; Stec, D. Org. Magn. Reson. 1984,
22, 301. (c) Davalli, S.; Lunazzi, L.; Macciantelli, D. J . Org. Chem. 1991,
56, 1739.
(18) Oki, M. Applications of Dynamic NMR Spectroscopy to Organic
Chemistry; VCH: Deerfield Beach, 1985; p 306.
(20) Anet, F. A. L.; Basus, V. J . J . Magn. Reson. 1978, 32, 339.

Atropisomers of N-Aryl-tetrahydropyrimidines
J . Org. Chem., Vol. 66, No. 20, 2001 6683
derivative 3 (16.6 vs 14.2 kcal mol-1). In the latter process
the steric hindrance acts evidently in the opposite sense,
enhancing the energy of the rotation transition state
more than that of the corresponding ground state.
Con clu sion s
Three different dynamic processes have been detected,
and the corresponding barriers measured, by dynamic
NMR in some N-aryl-substituted tetrahydropyrimidines,
namely enantiomerization of stereolabile atropisomers,
topomerization about the Ph-C axis and, presumably,
ring inversion of the six-membered ring. The X-ray
determined structure of one such a derivative is in good
agreement with that obtained by computation, thus
making the conformation and the stereodynamic assign-
ments carried out by theoretical methods reliable.
Exp er im en ta l Section
Ma t er ia l. 1-Aryl-2-substituted-1,4,5,6-tetrahydropyrim-
idines 1-4 were synthesized by ring closure of the correspond-
ing N-acyl-N′-aryltrimethylenediamines.22-24 Yields and physi-
cal data of new compounds are reported as Supporting
Information.
X-r a y Diffr a ction . Crystal data for 1-(2-chlorophenyl)-2-
phenyl-1,4,5,6-tetrahydropyrimidine (1): C16H15ClN2 (270.75),
monoclinic, Space group P21/c, Z ) 4, a ) 13.9710(9), b )
9.3524(6), c ) 11.1445(7) Å, â ) 100.718(2), V ) 1430.76(16)
F igu r e 7. Above -150 °C the 1H NMR spectrum of 4 (300
MHz in CHF2Cl) displays a single line for the hydrogens of
the tert-butyl group (top). Below -150 °C (bottom) the restric-
tion of a dynamic process (presumably ring inversion) makes
visible the signals due to a major and a minor conformer (in
about a 93:7 ratio)
3
Å , Dc ) 1.257 g cm-3, F(000) ) 568, µMo) 0.255 cm-1, T )
293 K. Data were collected using a graphite monochromated
Mo-KR X-radiation (λ ) 0.71073 Å) in the range 1.48° < θ <
30.17°. Of 18657 reflections measured, 4199 were found to be
independent (Rint ) 0.0487), 2177 of which were considered
as observed [I > 2σ(I)], and were used in the refinement of
172 parameters leading to a final R1 of 0.0443 and a Rall of
0.0861. The structure was solved by direct method and refined
by full-matrix least squares on F2, using SHELXTL 97
program packages. In refinements were used weights accord-
ing to the scheme w ) [σ2(Fo2) + (0.0650P)2 + 0.0000P]-1 where
P ) (Fo2) + 2Fc2)/3. The hydrogen atoms were located by
geometrical calculations and refined using a “riding” method.
wR2 was equal to 0.1207. The goodness of fit parameters S
was 0.843. Largest difference density between peak and hole
was 0.306 and -0.330 eÅ-3. Crystallographic data (excluding
structure factors and including selected torsion angles) have
been deposited with the Cambridge Crystallographic Data
Center, CCDC 166141.
bearing a substituent which would display a very intense
NMR signal. In this way even a small amount of the
minor conformer would yield a detectable signal, par-
ticularly if such a substituent is appropriately selected
as to allow the use of the much more sensitive 1H
frequency. The o-nitro phenyl derivative having a tert-
butyl group at position 2 of the tetrahydropyrimidine ring
(4) turned out to be well suited for such a purpose.
NMR Mea su r em en ts. The assignment of the signals was
obtained by means of DEPT, gHSQC, and gHMBC sequences
carried out in a 400 MHz spectrometer. The samples for the
low-temperature measurements were prepared by connecting
to a vacuum line the NMR tubes containing the desired
compounds dissolved in some C6D6 or CD2Cl2 for locking
purpose and condensing therein the gaseous solvents by means
of liquid nitrogen. The tubes were subsequently sealed in vacuo
and introduced into the precooled probe of the 300 MHz
spectrometer operating at 75.45 MHz for 13C or 400 MHz
operating at 100.6 MHz for 13C. The temperatures were
calibrated by substituting the sample with a precision Cu/Ni
thermocouple before the measurements. Total line shape
simulations were achieved by using a PC version of the
DNMR-6 program.11 Since at the low temperatures required
to observe the exchange process the intrinsic line width of the
compounds was significantly temperature dependent, the
corresponding dependence of the solvent signal was measured.
The appropriate ratio with the line width of the compound was
1
As shown in Figure 7, at -154 °C the single H NMR
line of the nine tert-butyl hydrogens splits into a pair of
signals separated by 0.125 ppm, their relative proportion
being approximately 93:7.
A barrier of 6.0 kcal mol-1 for the corresponding
dynamic process was obtained by line-shape simulation
(Table 1). If, as previously discussed, this motion is
assigned to ring inversion, the lower ∆Gq value measured
in 4 with respect to the corresponding derivative 3 (6.0
vs 7.3 kcal mol-1) should be a consequence of the steric
effect of the tert-butyl moiety. This group would enhance
the ground-state energy of the pyrimidine ring more than
that of the transition state.21 On the contrary, the tert-
butyl group in 4 would increase the enantiomerization
barrier with respect to that of the analogous phenyl
(22) Orelli, L.R.; Niemevz, F.; Garcia, M. B.; Perillo, I. A. J .
Heterocycl. Chem. 1999, 36, 105.
(23) Perillo, I. A.; Lamdan, S. J . Heterocycl. Chem. 1973, 10, 915.
(24) Orelli, L. R.; Garcia, M. B.; Niemevz, F.; Perillo, I. A. Synth.
Commun. 1999, 11, 1819.
(21) The same trend also results from Molecular Mechanics calcula-
tions (MMX force field13) where the computed barrier for the ring
inversion process in 2 was found lower than in 4 (8.8 and 11.1 kcal
mol-1, respectively).

6684 J . Org. Chem., Vol. 66, No. 20, 2001
Garcia et al.
then taken into account. We also checked that errors as large
as 50% on this value affected the activation energy by less than
0.05 kcal mol-1 in the temperature range investigated.25
preparation of some intermediates. Financial support
was received by MURST (national project “Stereoselec-
tion in Organic Synthesis”) and by the University of
Bologna (Funds for selected research topics 1999-2001).
Ack n ow led gm en t. Thanks are due to the CNR
I.Co.C.E.A. Institute (Bologna) for access to the 400
MHz spectrometer. We also acknowledge the help of
Farm. M. L. Magri and Mr. J . A. Bisceglia for the
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 1-4 and intermediates. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Grilli, S.; Lunazzi, L.; Mazzanti, A. J . Org. Chem. 2000, 65,
3563.
J O015743X