Chair to boat interconversion and face to face interactions in isomeric aryl-substituted perhydrocyclopentaquinolizines

Article abstract of DOI:10.1021/jo702172u

(Graph Presented) The structure and the conformation of the two isomeric 3,5-di(4-methoxyphenyl)perhydrocyclopenta[ij]-quinolizines 1 and 2 have been determined by a combination of NOE experiments, analysis of vicinal J coupling constants, and DFT computations. The two aryl rings were found to exhibit a face to face disposition, and variable-temperature NMR spectra allowed the determination of the corresponding rotation barriers, as well as chair to boat and nitrogen inversion processes of the quinolizine rings. The structure and the conformation of the two corresponding ammonium salts 1-H⁺ and 2-H⁺ were also obtained in solution by the same techniques: in addition, their solid-state structures were determined by X-ray diffraction.

Full text of DOI:10.1021/jo702172u

Chair to Boat Interconversion and Face to Face Interactions in
Isomeric Aryl-Substituted Perhydrocyclopentaquinolizines
Lodovico Lunazzi,§ Andrea Mazzanti,*,§ Shaik Rafi,¶ and H. Surya Prakash Rao¶
Department of Organic Chemistry “A. Mangini”, UniVersity of Bologna, Viale Risorgimento, 4 Bologna
40136, Italy, and Department of Chemistry, Pondicherry UniVersity, Puducherry 605014 India
mazzand@ms.fci.unibo.it
ReceiVed October 8, 2007
The structure and the conformation of the two isomeric 3,5-di(4-methoxyphenyl)perhydrocyclopenta[ij]-
quinolizines 1 and 2 have been determined by a combination of NOE experiments, analysis of vicinal J
coupling constants, and DFT computations. The two aryl rings were found to exhibit a face to face
disposition, and variable-temperature NMR spectra allowed the determination of the corresponding rotation
barriers, as well as chair to boat and nitrogen inversion processes of the quinolizine rings. The structure
and the conformation of the two corresponding ammonium salts 1-H+ and 2-H+ were also obtained in
solution by the same techniques: in addition, their solid-state structures were determined by X-ray
diffraction.
Introduction
of this type were also determined in the case of aryl groups
bonded, in a stacked arrangement, to other rigid frameworks
such as anthracene,5 cyclobutane,6 and acenaphthene.7
Aryl groups bonded to peri positions of a planar framework,
like 1,8-disubstituted naphthalene, adopt a face to face (stacked)
arrangement and display restricted rotation about the aryl
naphthalene bond that, in particular cases, might have a
sufficiently high barrier to produce configurationally stable cis
and trans isomers.1 A number of barriers for the interconversion
of these types of isomers have been reported.2 When the aryl
substituents are not sufficiently large, stereolabile isomers
(conformers) have often been observed and the corresponding
interconversion barriers determined by variable-temperature
NMR spectroscopy.3 Heterocyclic rings bonded to the 1,8-
positions of naphthalene displayed analogous features.4 Barriers
Here we present a quite peculiar situation where two aryl
rings are bonded to the less rigid framework of perhydrocy-
(3) (a) House, H. O.; Campbell, W. J.; Gil, M. J. Org. Chem. 1970, 35,
1815. (b) Anderson, J. E.; Cooksey, C. J. Chem. Commun. 1975, 942. (c)
Cosmo, R.; Sternhell, S. Aust. J. Chem. 1987, 40, 1107. (d) Cozzi, F.;
Ponzini, F.; Annunziata, R.; Cinquini, M.; Siegel, J. S. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1019. (e) Thirsk, C.; Hawkes, G. E.; Kroemer, R. T.;
Liedl, K. R.; Loerting, T.; Nasser, R.; Pritchard, R. G.; Steele, M.; Warren,
J. E.; Whiting, A. J. Chem. Soc., Perkin Trans. 2 2002, 1510.
(4) (a) Zoltewicz, J. A.; Maier, N. M.; Fabian, W. M. F. J. Org. Chem.
2006, 71, 7018. (b) Wolf, C.; Ghebremariam, B. T. Tetrahedron: Asymmetry
2002, 13, 1153. (c) Zoltewicz, J. A.; Maier, N. M.; Fabian, W. M. F.
Tetrahedron 1996, 52, 8703. (d) Nakagawa, Y.; Honda, K.; Nakanishi, H.
Magn. Reson. Chem. 1996, 34, 78.
§ University of Bologna.
¶ Pondicherry University.
(1) Clough, J. D.; Roberts, J. D. J. Am. Chem. Soc. 1976, 98, 1018.
(2) (a) Cozzi, F.; Cinquini, M.; Annunziata, R.; Dwyer, T.; Siegel, J. S.
J. Am. Chem. Soc. 1992, 114, 5729. (b) Cozzi, F.; Cinquini, M.; Annunziata,
R.; Siegel, J. S. J. Am. Chem. Soc. 1993, 115, 5330. (c) Tumambac, G. E.;
Wolf, C. J. Org. Chem. 2005, 70, 2930.
(5) Lunazzi, L.; Mancinelli, M.; Mazzanti, A. J. Org. Chem. 2007, 72,
5391 and references quoted therein.
(6) Ben-Efraim, D. A.; Arad-Yellin, R. J. Chem. Soc., Perkin Trans. 2
1994, 853.
(7) Lai, Y.-H.; Chen, P. J. Chem. Soc., Perkin Trans. 2 1989, 1665.
10.1021/jo702172u CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/22/2007
678
J. Org. Chem. 2008, 73, 678-688

Aryl-Substituted Perhydrocyclopentaquinolizines
SCHEME 1
CHART 1
conversion of the molecule to the corresponding ammonium
salt, in effect making the system more similar to trans-decalins.
Dynamic NMR spectroscopic analysis can be used to evaluate
the conformational changes involving, possibly, nitrogen inver-
sion, ring inversion, and restricted rotation of the aryl rings in
quinolizidines of the types 1 and 2. Since the basic cyclopenta-
[i,j]quinolizidine structural motif is encountered in the structure
of a number of complex alkaloids such as vallesamidine,13
callichiline,14 criophylline,15 and schizozygine,16 studies of the
conformational dynamics involved in such systems can be quite
useful from the point of view of structure-activity relationships.
clopentaquinolizine8 (see compounds 1 and 2 of Chart 1, where
methoxy groups in the para position of the aryl rings serve to
simplify NMR spectra). Thus, in addition to the rotation process
involving these anisole substituents attached to a more flexible
ring system, the inversion processes occurring within the
perhydrocyclopentaquinolizine moiety should also be observed.
Results and Discussion
Amines 1 and 2. The structure of amine 1 (Chart 1) was
investigated by NOE experiments and was found to correspond
to a cis,cis ring junction8b at the perhydrocyclopentaquinolizine
moiety. As reported in Figure S1 of Supporting Information,
irradiation of the triplet of H9b (at 2.88 ppm) yields NOE effects
on the pair of hydrogens 3,5 (at 3.24 ppm), on the pair of
hydrogens 7a,9a (at 2.28 ppm), and on the hydrogens 1,7 (at
1.71 and 1.55 ppm). On the contrary, NOE was not observed
on H8,H9 (1.84 and 2.02 ppm) nor on the aromatic hydrogens.
These results were further confirmed by the irradiation of the
H3,H5 triplet.
A complete conformational search for this type of structure
was carried out by molecular mechanics force field (MMFF)
measurements,17 and the two most stable conformers were
subsequently minimized by DFT computations.18 In Figure 1
(top left) is displayed the preferred conformation (its energy is
In the perhydroquinolizine (quinolizidine) framework, which
is well-represented among many physiologically active alka-
loids,9 a nitrogen atom replaces the carbon C-4a of cis- or trans-
decalins (perhydronaphthalenes), as displayed in Scheme 1. The
framework of trans-decalin is locked, as it cannot invert to an
alternative chair-chair system unless carbon-carbon bonds are
broken and then rejoined;10 on the contrary, cis-decalin can
interconvert between two chair-chair conformations, even at
ambient temperature. As shown in Scheme 1, and in contrast
to the conformational rigidity of trans-decalin, the trans-
quinolizidine can interconvert from one chair-chair conforma-
tion to other chair-chair conformations via cis-quinolizidine.
This is possible since nitrogen inverts its configuration and, since
this process is faster than chair-to-chair exchange in pip-
eridines,11 it is likely that trans-quinolizidines interconvert
rapidly to another form at ambient temperature.12 Equilibration
of chair conformations in quinolizidines can be prevented by
adding a bridging ring such as that of cyclopenta[i,j]quinoliz-
idines 1 and 2 in Chart 1 or by blocking nitrogen inversion by
(13) Dickman, D. A.; Heathcock, C. A. J. Am. Chem. Soc. 1989, 111,
1528.
(14) Mcphail, A. T.; Poisson, J. Tetrahedron 1983, 39, 3629.
(15) Seok kam, T.; Yeng loh, K.; Chen, W. J. Nat. Prod. 1993, 56, 1865.
(16) Renner, U.; Kernweisz, P. Experentia 1963, 19, 244.
(17) MMFF, as implemented in Titan 1.0.5, Wavefunction Inc.: Irvine,
CA. A Monte Carlo algorithm (version 1.0.3) was used for locating the
global minima.
(8) (a) Rao, H. S. H.; Jeyalakshmi, K.; Senthilkumar, S. P. Tetrahedron
2002, 58, 2189. (b) It has to be pointed out that the nomenclatures for the
perhydrocyclopentaquinolizine ring junctions displayed in Scheme 7 of ref
8a are in error and must be interchanged, that is, the picture called trans,trans
is actually cis,cis and vice versa.
(9) Alkaloids: Biochemistry, Ecology and Medicinal Applications;
Roberts, M. F., Wink, M., Eds.; Springer: New York, 1998.
(10) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley-Interscience: Kundli, 2003; pp 776-777.
(11) (a) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure,
Preparation, ReactiVity and Synthetic Applications of Piperidine and its
DeriVatiVes; Elsevier: Amsterdam, 1991. (b) Anet, F. A. L.; Yavari, I. J.
Am. Chem. Soc. 1977, 99, 2794.
(18) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, revision D.01; Gaussian, Inc.: Wallingford, CT, 2004 (see Supporting
Information).
(12) (a) Moyneh, T. M.; Schofield, K.; Jones, R. A.; Katritzky, A. R. J.
Chem. Soc. 1962, 2637. (b) Sugiura, M.; Sasaki, Y. Chem. Pharm. Bull.
1976, 22, 2988. (c) Lalonde, R. T.; Donvito, T. N. Can. J. Chem. 1974, 52,
3778. (d) Slough, G. A.; Han, F.; Lee, B. H. Tetrahedron Lett. 1999, 40,
3851 .
J. Org. Chem, Vol. 73, No. 2, 2008 679

Lunazzi et al.
FIGURE 2. Left: Temperature dependence of the 13C signal (150.8
MHz in CD2Cl2) of the aromatic carbons meta to the OMe group
(position 11) of compound 1. Right: Computer simulation with the
rate constants reported.
in the Karplus equation,20 they yield vicinal J couplings of 3.7
and 4.9 Hz. Due to the mentioned rapid interconversion at
ambient temperature, the average J becomes 4.3 Hz. We also
calculated these vicinal J couplings by making direct use of
the DFT approach18 (including the Fermi contact contribution),
thus avoiding the application of the empirical Karplus equa-
tion: the values obtained in this way were found to be 4.6 and
5.6 Hz, yielding an average J coupling of 5.2 Hz. By taking
into account the two theoretical approaches (that define a range
of 4.3-5.2 Hz), we can predict a value of 4.7 ( 0.5 Hz for this
J coupling (Table 1), which fits well with the experimental value
(4.5 Hz).21
FIGURE 1. Top: DFT-computed structure (left) of the preferred
conformer of 1 (arbitrarily selected as 3S,5R,7aR,9aS). The exchange
with its mirror image yields a dynamic Cs symmetry (right) with the
aryl rings syn to the five-membered ring (i.e., in the same average
pseudoequatorial positions). Bottom: DFT-computed structure (left)
of the preferred conformer of 2 (arbitrarily selected as 3R,5S,7aR,-
9aS). The exchange with its mirror image yields a dynamic Cs symmetry
(right) with the aryl rings anti to the five-membered ring (i.e., in the
same average pseudoaxial positions). The arrows indicate the large NOE
effects experimentally observed.
1.9 kcal mol-1 lower than that of the second most stable form
where both the six-membered rings are chairs), where one of
the two six-membered rings is a chair and the other is a twisted-
boat.19 Such a static conformer exists as two enantiomeric forms
that interconvert rapidly at ambient temperature yielding a
dynamic Cs symmetry which accounts for the equivalence of
the pairs of the 13C lines in the corresponding spectrum at 25 °C
(Supporting Information).
(22) As often observed in conformational processes, the free energy of
activation was found independent of temperature within the errors, indicating
a negligible value of ∆Sq. See, for instance: (a) Dondoni, A.; Lunazzi, L.;
Giorgianni, P.; Macciantelli, D. J. Org. Chem. 1975, 40, 2979. (b)
Hoogosian, S.; Bushweller, C. H.; Anderson, W. G.; Kigsley, G. J. Phys.
Chem. 1976, 80, 643. (c) Lunazzi, L.; Cerioni, G.; Ingold, K. U. J. Am.
Chem. Soc. 1976, 98, 7484. (d) Lunazzi, L.; Dondoni, A.; Barbaro, G.;
Macciantelli, D. Tetrahedron Lett. 1977, 18, 1079. (e) Forlani, L.; Lunazzi
L.; Medici, A. Tetrahedron Lett. 1977, 18, 4525. (f) Bernardi, F.; Lunazzi,
L.; Zanirato, P.; Cerioni, G. Tetrahedron 1977, 33, 1337. (g) Lunazzi, L.;
Magagnoli, C.; Guerra, M.; Macciantelli, D. Tetrahedron Lett. 1979, 20,
3031. (h) Cremonini, M. A.; Lunazzi, L.; Placucci, G.; Okazaki, R.;
Yamamoto, G. J. Am. Chem. Soc. 1990, 112, 2915. (i) Anderson, J. E.;
Tocher, D. A.; Casarini, D.; Lunazzi, L. J. Org. Chem. 1991, 56, 1731. (j)
Gribble, G. W.; Olson, E. R.; Brown, J. H.; Bushweller, C. H. J. Org. Chem.
1993, 58, 1631. (k) Borghi, R.; Lunazzi, L.; Placucci, G.; Cerioni, G.;
Foresti, E.; Plumitallo, A. J. Org. Chem. 1997, 62, 4924. (l) Garcia, M. B.;
Grilli, S.; Lunazzi, L.; Mazzanti, A.; Orelli, L. R. J. Org. Chem. 2001, 66,
6679. (m) Garcia, M.B.; Grilli, S.; Lunazzi, L.; Mazzanti, A.; Orelli, L. R.
Eur. J. Org. Chem. 2002, 4018. (n) Anderson, J. E.; de Meijere, A.;
Kozhushkov, S. I.; Lunazzi, L.; Mazzanti, A. J. Am. Chem. Soc. 2002, 124,
6706. (o) Casarini, D.; Rosini, C.; Grilli, S; Lunazzi, L.; Mazzanti, A. J.
Org. Chem. 2003, 68, 1815. (p) Casarini, D.; Grilli, S.; Lunazzi, L.;
Mazzanti, A. J. Org. Chem. 2004, 69, 345. (q) Bartoli, G.; Lunazzi, L.;
Massacesi, M.; Mazzanti, A. J. Org. Chem. 2004, 69, 821. (r) Casarini, D.;
Coluccini, C.; Lunazzi, L.; Mazzanti, A.; Rompietti, R. J. Org. Chem. 2004,
69, 5746.
The DFT computed H-C9b-C9a-H and H-C9b-C7a-H
dihedral angles are 46 and 38°, respectively: when introduced
(19) The twist-boat conformation has been found to occur in a number
of six-membered rings; see: (a) Bushweller, C. H. J. Am. Chem. Soc. 1969,
91, 6019. (b) Weiser, J.; Golan, O.; Fitjer, L.; Biali, S. E. J. Org. Chem.
1996, 61, 8277. (c) Gill, G.; Pawar, D. M.; Noe, E. A. J. Org. Chem. 2005,
70, 10726. (d) Thanikasalam, K.; Jeyaraman, R.; Panchanatheswaran, K.;
Low, J. N.; Glidwell, C. Acta Crystallogr. 2006, C62, o324.
(20) Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870.
(21) Except for the presence of the two OMe groups, compound 1
corresponds to that indicated as 30 (amount 58%) in ref 8a (both have, in
fact, very similar NMR parameters for the perhydrocyclopentaquinolizine
moiety). On the basis of the present results, the structure of the latter should
be therefore corrected and the same structure of compound 1 should be
assigned.
680 J. Org. Chem., Vol. 73, No. 2, 2008

Aryl-Substituted Perhydrocyclopentaquinolizines
FIGURE 3. Temperature dependence of the 13C signals (150.8 MHz
in CD2Cl2) of the aliphatic carbons at positions 3,5 and 9b (65.5 and
62.8 ppm at -35 °C, respectively) of compound 1 (left). The line of
the single carbon at position 9b is not sensitive to the internal motion
and, therefore, was not included in the simulation (right).
FIGURE 4. Temperature dependence of the 13C signal (150.8 MHz
in CHF2Cl/CHFCl2) of the carbons para to the OMe group (C10) of
compound 2, which splits into a 1:1 doublet at -141 °C, whereas that
of the carbons meta to the OMe group (C11) splits into three lines
(1:2:1 ratio) at the same temperature. The simulations were obtained
with the rate constants reported.
TABLE 1. Experimental Values and Computed Ranges for the
Vicinal J Couplings (Hz) Involving the Hydrogen at Position 9b
vicinal JHCCH
vicinal JHNCH
compound
experimental computed experimental
computed
1
2
4.5
8.4
4.4
9.2
5.0
4.7 ( 0.5
8.6 ( 1.5
4.4 ( 1.3
8.8 ( 1.8
5.2 ( 1.7
TABLE 2. Experimental and DFT-Computed Barriers (kcal
mol-1) for 1 and 2
1-H+
8.7
4.9
11.6
11.5 ( 0.1
5.9 ( 1.0
11.8 ( 0.2
2-H+ (major)
2-H+ (minor)
ring inversion
aryl rotation
experimental computed
12.55 14.2
compound experimental computed
The 13C spectrum of 1 (150.8 MHz in CD2Cl2) shows a broad
signal (ca. 129.5 ppm) for the CH carbons in the meta position
to OMe (C11); on lowering the temperature (Figure 2), this
signal broadens further and eventually splits into a pair of
equally intense integrated lines (the same occurs for the C12
line, ortho to the OMe group, although with a lower shift
separation).
This process is due to the restricted rotation of the aryl rings,
and from the rate constants obtained by line shape simulation,
a ∆Gq value of 12.55 kcal mol-1 was derived22 (Table 2).
On further lowering the temperature, almost all of the 13C
lines broaden, and at -100 °C, they split into pairs; in particular,
1
2
8.6
7.0
9.6
5.6
not measurablea aryl A: 13.3
aryl B: 2.1
a See text.
the aromatic carbons at position 11, which yielded two lines at
-36 °C, as shown in Figure 2, exhibit four lines at -100 °C,
as do the aromatic carbons at position 12 (Figure S2 of
Supporting Information). As an example, the trace of Figure 3
displays the splitting of the line due to the pair of carbons at
positions 3,5, whereas the single line of the carbon at position
9b, obviously, does not split. This process is due to the slow
inversion of the six-membered rings, which has a free energy
of activation of 8.6 kcal mol-1 (Table 2), as obtained from the
rate constants reported in the simulated spectra
(23) The experimental rate constants are relative to the motion of both
the six-membered rings, thus the motion of a single ring corresponds to
half the rate constants reported. It is thus the ∆Gq obtained from 1/2 k
values that should, in principle, be compared to the theoretical value of 9.6
kcal mol-1. The ∆Gq obtained in this way (8.9 kcal mol-1) is in even better
agreement with the theory. See: Lunazzi, L.; Mazzanti, A.; Minzoni, M. J.
Org. Chem. 2007, 72, 2501.
(24) This process does not correspond to the typical chair to chair
inversion (where the axial substituents become equatorial) since here the
twist-boat becomes a chair and vice versa (see: Kolossovary, I.; Guisa, W.
J. Am. Chem. Soc. 1993, 115, 2107), keeping the aryl substituents in the
pseudoequatorial situation (i.e., syn to the five-membered ring).
In order to better understand the nature of this inversion
process, a search for the corresponding transition state was
(25) The degree of pyramidalization is defined as 360°-∑RNR and
covers the range of 40 (for a nearly perfect pyramidal nitrogen, as that of
NH3) to 0° (for a perfectly planar nitrogen). In the case of acyclic three-
alkyl amines (such as NMe3), this degree is about 27°, and it is somewhat
lower in the case of cyclic three-alkyl amines; see: Ganguly, B.; Freed, D.
A.; Kozlowski, M. C. J. Org. Chem. 2001, 66, 1103.
J. Org. Chem, Vol. 73, No. 2, 2008 681

Lunazzi et al.
carried out by means of DFT computations. This structure
(reported in Figure S3 of Supporting Information) has a
computed energy 9.6 kcal mol-1 higher than that of the ground
state of Figure 1. Such a value is in fair agreement with the
measured barrier23 and indicates that the transition state corre-
sponds to the transformation of the twist-boat six-membered
ring into a chair and vice versa.24 This process, apparently, does
not involve a significant inversion of the nitrogen atom; the
latter, in fact, has essentially the same degree of pyramidaliza-
tion25 in the ground and in the transition states, with these values
being 23.4 and 22.4°, respectively.
Likewise, we used DFT calculations to identify the transition
state that accounts for the rotation of the aryl rings. The structure
for the corresponding transition state was found to have a
computed energy 14.2 kcal mol-1 (Table 2) higher than that of
the ground state, again in satisfactory agreement with the
experimental barrier.26 These calculations indicate that, in order
to make sufficient space to accomplish the rotation of the
aromatic rings, a flattening of the nitrogen atom is also
required.27 In this transition state, in fact, the latter is computed
to be almost planar, its degree of pyramidalization25 being 5.2°
(see Figure S3 of Supporting Information).
The structure of the isomeric compound 2 was also obtained
by means of NOE experiments that indicate the same type of
cis,cis junction for the perhydrocyclopentaquinolizine moiety
since, as in the case of 1, irradiation of the H9b triplet enhances
the signal of the hydrogens at positions 7a,9a (Figure S4 of
Supporting Information). Here the two aryl groups are anti to
the five-membered ring (i.e., in a dynamic pseudoaxial position)
since irradiation of the H9b triplet enhances the aromatic
hydrogens in a meta position to the OMe group (position 11)
and yields a very small effect on the signals of H3,H5, contrary
to the case of 1 (Figure S4 of Supporting Information).
The two most stable conformers of the above structure28 were
identified by DFT computations,18 and in Figure 1 (bottom left),
the preferred conformation is displayed (its energy being 1.1
kcal mol-1 lower than that of the second most stable form, where
both of the six-membered rings are chairs). As it appears in
Figure 1, the two six-membered rings of the static conformer
are different because one is a chair and the other is essentially
a boat. Accordingly, the perhydrocyclopentaquinolizine moiety
has a different shape than in the case of 1, and for this reason,
the corresponding H-C9b-C9a-H and H-C9b-C7a-H
dihedral angles are significantly smaller (i.e., 31 and 3.5°,
respectively). From the Karplus equation,12 the related J
couplings become 5.9 and 8.2 Hz, respectively, and the average
value, resulting from the fast inversion process, is thus 7.05 Hz.
The direct DFT determination18 of these couplings yields an
average value of 10.1 Hz (resulting from 8.4 and 11.8 Hz). By
taking into account these two approaches (that define a range
of 7.05-10.1 Hz), a vicinal J coupling of 8.6 ( 1.5 Hz is
predicted (Table 1), in agreement with the experimental value
of 8.4 Hz.29
Therefore, the structures proposed for 1 and 2 on the basis
of the NOE experiments also account for the observation of a
vicinal J coupling larger in 2 with respect to 1, although both
compounds have the same type of cis,cis ring junction.
Like in the case of 1, the 13C signals of 2 also broaden on
cooling and eventually yield a greater number of sharp lines,
owing to the restriction of the internal motions. As an example,
in Figure 4 is reported the temperature dependence of the signals
of the quaternary aromatic carbon in the para position to OMe
(C10) and of the aromatic CH carbon in the meta position to
OMe (C11). The carbons at position 10 have the corresponding
signal insensitive to the aryl rotation because they lie on the
rotation axis of the aryl moiety, thus the observed 1:1 splitting
must be attributed solely to the restriction of ring inversion,
the corresponding barrier, obtained from the rate constants of
Figure 4, being 7.0 kcal mol-1
.
The carbons at position 11, on the other hand, have the
corresponding signal sensitive to both rotation and inversion
processes and should yield, in principle, two doublets (as
observed for compound 1). Contrary to the case of 1, however,
only three lines, with a 1:2:1 intensity ratio, are observed below
-140 °C (Figure 4), suggesting that the rotation process of one
of the two aryl groups is frozen at this temperature, whereas
the other is not. This was confirmed by the observation that
the C-12 signal also splits into three lines with the same 1:2:1
intensity pattern. The first and the third lines of C11 in Figure
4 (130.3 and 127.4 ppm, respectively) are those of the two
diastereotopic carbons of the aryl group which does not rotate
anymore, whereas the two-fold intense central line (129.5 ppm)
is that of the two equivalent carbons of the aryl group which is
still in the fast rotation mode. The line shape simulation of these
three lines was obtained without a direct exchange rate between
the first and third line (i.e., the rate corresponding to the aryl
rotation); their exchange occurred through the intermediacy of
the ring inversion rate, as shown by the fact that the same values
of the rate constants used to simulate the exchange of the C10
lines were also employed. This situation, therefore, corresponds
to that observed in the cases of exchange processes that, in spite
of the presence of a higher barrier, are nevertheless NMR
invisible until a second process, with a lower barrier, is also
frozen.30,31 In this case, the rotation of one of the two aryl groups
has a barrier higher than ring inversion but can be observed
only when the latter process (which is the rate-limiting process)
is also frozen; this means that the high rotation barrier cannot
be experimentally determined. The lower rotation barrier of the
other aryl group, on the other hand, cannot be determined for
a different reason, that is, because its value is too low for an
NMR measurement. The following computational results help
in understanding this type of stereodynamics.
The DFT-computed transition state for the ring inversion
process indicates that, in order to transform the chair into a boat
(29) Except for the presence of the two OMe groups, compound 2
corresponds to that indicated as 31 (29%) in ref 8a (both have, in fact, very
similar NMR parameters for the perhydrocyclopentaquinolizine moiety).
On the basis of the present results, the structure of the latter should be
therefore corrected and the same structure of compound 2 should be
assigned.
(26) As discussed in ref 15, the barrier for the rotation of a single aryl
ring becomes 13.0 kcal mol-1, again in better agreement with the theory
(14.2 kcal mol-1).
(27) Such a flattening does not seem to correspond to a nitrogen inversion
process, in that the nitrogen atom comes back, apparently, to the same initial
pyramidal arrangement.
(28) Actually, there is also a computed minimum with an energy 0.4
kcal mol-1 higher than that of the ground state, but this corresponds to a
conformer having the same arrangement for the three fused rings shown in
Figure 1 and differing solely by the torsion angles of the two aryl groups
(62 and 54° rather than 13 and 52°).
(30) Such a situation, for instance, has been encountered in some aliphatic
amines where the larger C-N rotation barrier is NMR invisible until the N
inversion, which has a lower barrier, is also frozen; see: Jackson, W. R.;
Jennings, W. B. Tetrahedron Lett. 1974, 15, 1837.
(31) (a) Anderson, J. E.; Casarini, D.; Ijeh, A. J.; Lunazzi, L. J. Am.
Chem. Soc. 1997, 119, 8050. (b) Casarini, D.; Lunazzi, L.; Mazzanti, A.;
Foresti, E. J. Org. Chem. 1998, 63, 4746. (c) Lunazzi, L.; Mazzanti, A.;
AÄ lvarez Mun˜oz, A. J. Org. Chem. 2000, 65, 3200.
682 J. Org. Chem., Vol. 73, No. 2, 2008

Aryl-Substituted Perhydrocyclopentaquinolizines
FIGURE 5. Single-crystal X-ray diffraction structure of the ammonium salt 1-H+ (top). Underneath are reported the two most stable DFT-
computed conformers, with the relative energies (E) in kcal mol-1. In the computations, the presence of the CF3COO- anion has been neglected
for convenience.
(and vice versa), a concomitant nitrogen inversion is also
required; in the course of this process, in fact, the nitrogen atom
inverts through an essentially planar state having a degree of
pyramidalization of 2.2° (see Figure S5 of Supporting Informa-
tion). The energy for this transition state, computed with respect
to the ground state, is 5.6 kcal mol-1, a value lower than that
computed (9.6 kcal mol-1) in the case of 1. This result parallels
the experimental determination that yields an inversion barrier
for 2 lower than that for 1 (i.e., 7.0 vs 8.6 kcal mol-1, as in
Table 2).
In the static conformation of 2 (reported in Figure 1),
the two aryl groups (labeled A and B) are in very different
positions, contrary to the case of 1; the rotation transition
state of one of them (aryl A in Figure S5 of Supporting
Information) is computed to have an energy of about 13.3 kcal
mol-1 (i.e., similar to that of 1), while that of the other (aryl B)
is only 2.1 kcal mol-1. The latter is too low for an NMR
determination, thus one of the two aryl groups will always
display, at any attainable temperature, a single line for the
corresponding carbons at position 11, as experimentally ob-
served.
becomes very fast and, for this reason, cannot display the shift
differences for its C11 lines; this will only occur when the ring
inversion process, which restores the identity of the aryl A, is
also frozen. The kinetic is controlled, in practice, by the process
with the lower of the two barriers30,31 (i.e., ring inversion), so
that the higher barrier, for the rotation of aryl A, cannot be
determined by NMR (Table 2).
Ammonium Salts 1-H+ and 2-H+. When treated with 1
equiv of CF3COOH, compound 1 yields the corresponding
ammonium salt (1-H+). Its NMR spectrum displays essentially
the same vicinal coupling (J ) 4.4 Hz) as that of 1 for
the hydrogen at position 9b, with the latter being, in addition,
coupled with the NH+ hydrogen (J ) 8.7 Hz). Also, the patterns
of the NOE experiments32 (Figure S6 of Supporting Infor-
(32) The NOE experiments were carried out at -10°C since the
spectrum displays a better resolution than at ambient temperature. This
depends on the fact that in a CD2Cl2 solution the salt 1-H+ appears to
experience an exchange process with a form which is present in such a
small amount (less than 1%) as to be NMR invisible (possibly the form
where the N-H+ bond is synclinal, rather than antiperiplanar, to the H-C9b
bond). At -10 °C, the rate of this process becomes sufficiently slow as to
make the lines of the salt sharper than at +25 °C. This is the well-known
effect occurring when there is an exchange process between two very biased
partners. See: (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. (c)
Lunazzi, L.; Mazzanti, A.; Casarini, D.; De Lucchi, O.; Fabris, F. J. Org.
Chem. 2000, 65, 883. The hypothesis of two forms for such a type of
ammonium salt will be better clarified in the case of the ammonium salt
2-H+.
Since the inversion barrier of the perhydrocyclopentaquino-
lizine ring is computed (and measured) to be much lower than
13.3 kcal mol-1, the aryl group A, with the higher rotation
barrier, exchanges rapidly its position with the aryl B (which
has the 2.1 kcal mol-1 rotation barrier). When this rapid A to
B exchange has occurred, the rotation of the former aryl A also
J. Org. Chem, Vol. 73, No. 2, 2008 683

Lunazzi et al.
mation) parallel those of 1; the value of the vicinal J coupling
and the NOE results thus indicate that the salt has the
same type of structure as the free amine 1; that is, the two aryl
groups in a pseudoequatorial position are syn to the five-
membered ring. This structure is confirmed by the single-crystal
X-ray diffraction of 1-H+ (Figure 5, top) that displays a
cis,cis junction at the perhydrocyclopentaquinolizine moiety,
with the NH+ hydrogen antiperiplanar to the hydrogen at
position 9b.
The solid-state conformation of the salt 1-H+ shows that both
of the six-membered rings adopt a chair disposition, whereas
the DFT calculations indicate that this corresponds to the second
most stable conformer, the preferred one (with a 1.4 kcal mol-1
lower energy) being that where one ring is a chair and the other
a twisted-boat, like amine 1. It is not unusual to encounter such
differences between the conformations in solids and in solution
that depend on the fact that the crystals privilege the conforma-
tion which fits better the crystal cell.33,34
The conformation adopted in solution, on the other hand,
corresponds to that predicted by calculations, as proven by low-
temperature NMR spectra. Below +5 °C, the 1H signals of the
aromatic hydrogens meta to OMe (position 11) decoalesce, in
fact, into a pair of signals, as shown in Figure S6 (trace a) of
Supporting Information. The aryl rotation barrier responsible
for this effect was found to be 12.25 kcal mol-1 (Table 3), a
value essentially equal, within the errors ((0.15 kcal mol-1),
to that determined for the amine 1. On further lowering the
temperature, a number of aliphatic 1H and 13C signals broaden
and eventually decoalesce at -130 °C, due to the freezing of
the ring inversion process; as an example, the splittings of the
CH carbons at positions 7a,9a and CH2 carbons at positions
2,6 are displayed in Figure 6. This feature proves that in 1-H+
the two six-membered rings are different, as predicted by
calculations (i.e., a twisted-boat and a chair), and not equal (two
chairs) as in the crystal.
FIGURE 6. Temperature dependence of the 13C signals (150.8 MHz
in CD2Cl2/CHF2Cl) of the CH and CH2 carbons of the ammonium salt
1-H+ at positions 7a,9a and 2,6.
TABLE 3. Experimental and DFT-Computed Barriers (kcal
mol-1) for the Ammonium Salts 1-H+ and 2-H+
ring inversion
aryl rotation
experimental
computeda
compound
experimental
computeda
1-H+
7.7
10.15
8.9
15.0
12.25
19.4
aryl A: 16.6
Furthermore, since a N-inversion process cannot occur in the
ammonium salt, this finding supports the theoretical prediction
that the ring inversion pathway (chair to twisted-boat and vice
versa) in amine 1 does not involve appreciable N inversion.
The value of the barrier measured for the ring inversion in 1-H+
(7.7 kcal mol-1, as in Table 3) is quite close to that of the
analogous process occurring in 1, the difference being only 0.9
2-H+
aryl A: -b
(major)
aryl B: 5.5
aryl B: 7.3
a In these computations, the anion CF3COO- has not been included. b Not
measureable, see text.
The sharpening of the lines at lower temperatures is an effect
analogous to that observed32 in 1-H+; in the present case,
however, the signals of the minor form, although quite small,
are clearly visible. The exchange between the two forms of the
salt can take place because the H+ of the N-H+ bond is quite
mobile in solution, so the corresponding bond can be broken at
ambient temperature, making it possible for H+ to be linked to
the nitrogen atom in two opposite positions, yielding, as a
consequence, a pair of isomeric ammonium salts having the
pyramid of nitrogen inverted.
We suggest that the structure of the major form should be
that where the N-H+ bond is in a synclinal relationship with
the H-C bond at position 9b, whereas the minor form should
correspond to the structure where the N-H+ bond is anti-
periplanar to the H-C9b bond. The DFT-computed structures
(Figure S8 of Supporting Information) indicate, in fact, that the
former structure (synclinal) is about 6 kcal mol-1 more stable35
than the latter (antiperiplanar).
kcal mol-1
.
Also the amine 2 yields the corresponding ammonium salt
(2-H+) when treated with 1 equiv of CF3COOH. The corre-
sponding room-temperature spectrum of this salt shows the
presence of two forms at the equilibrium; there are, in fact, two
spectral traces, with very different intensity, having the line
widths broadened by a mutual exchange process. When cooled
to -10 °C, in fact, these lines become sharper so that the signal
of the minor form could be integrated, indicating that its
proportion is 3 ( 0.3% (Figure S7 of Supporting Information).
(33) (a) Johansen, J. T.; Vallee, B. L. Proc. Natl. Acad. Sci. U.S.A. 1971,
68, 2532. (b) Kessler, H. Fresenius Z. Anal. Chem. 1987, 327, 66. (c) Burke,
L. P.; DeBellis, A. D.; Fuhrer, H.; Meier, H.; Pastor, S. D.; Rihs, G.; Rist,
G.; Rodebaugh, R. K.; P. Shum, S. P. J. Am. Chem. Soc. 1997, 119, 8313.
(d) Paulus, E. F.; Kurz, M.; Matter, H.; Ve´rtesy, L. J. Am. Chem. Soc.
1998, 120, 8209. (e) Coluccini, C.; Grilli, S.; Lunazzi, L.; Mazzanti, A. J.
Org. Chem. 2003, 68, 7266. (f) Perry, N. B.; Blunt, J. W.; Munro, M. H.
Magn. Reson. Chem. 2005, 27, 624.
(34) A situation where it has been unambiguously demonstrated that the
X-ray diffraction structure in the solids is that of the minor conformer present
in solution has been reported: Lunazzi, L.; Mazzanti, A.; Minzoni, M.;
Anderson, J. E. Org. Lett. 2005, 7, 1291.
Experimental support for this assignment was obtained by
means of NOE experiments. In particular, irradiation of the H9b
signal36 of the major form yields a very large enhancement of
684 J. Org. Chem., Vol. 73, No. 2, 2008

Aryl-Substituted Perhydrocyclopentaquinolizines
the NH+ signal at 10 ppm (Figure S7 of Supporting Information)
since the average interproton distance is computed to be as low
as 2.1 Å. On the other hand, irradiation of the signal of the two
equivalent H3,H5 hydrogens (Figure S7 of Supporting Informa-
tion) yields a much lower enhancement of the NH+ signal; the
corresponding average interproton distance is computed to be
2.64 Å, thus entailing an NOE effect smaller by a factor of
about 4 with respect to the previous one. Such a result (i.e., the
trend of the enhancement of the NH+ signal) is opposite to that
observed for 1-H+ (Figure S6, traces b and c), thus reinforcing
the conclusion that in the major form of 2-H+ the N-H+ and
the H-C9b bonds adopt a synclinal, rather than an antiperipla-
nar, relationship.
Independent support for this assignment is also obtained by
the analysis of the vicinal J coupling constants (Table 1).37,38
The major form (97%) of 2-H+ displays a J ) 9.2 Hz for the
vicinal coupling36 between H9b and the H7a, H9a pair (Table
1), that is, a value close to that (8.4 Hz) measured in the
corresponding amine 2. This suggests, therefore, that the salt
and the amine have the same type of structure (i.e., a cis,cis
junction) for the perhydrocyclopentaquinolizine moiety, with
the two aryl groups anti to the five-membered ring in a
pseudoaxial position. Indeed, the DFT-computed structure of
the lower energy form of 2-H+ (Figure S8 of Supporting
Information, left) is quite similar to the computed structure of
the corresponding amine 2 (Figure 1, bottom).
On lowering the temperature, the single 1H signal of the two
OMe groups of the major (97%) form broadens and splits into
a pair of equally intense lines at -93 °C, as in Figure S9 of
Supporting Information (the same occurs for the signal of the
hydrogens at positions 3 and 5). Since the signals of these
hydrogens are insensitive to the effect of the aryl rotation, the
observed dynamic process must be attributed to the restriction
of ring inversion. This agrees with the computations that show
how the two perhydroquinolizine rings have different shapes
in the major form, one being a chair and the other a boat (Figure
S8 of Supporting Information). The chair to boat interconversion
is fast at ambient temperature (making isochronous the signals
of the OMe as well of the H3,H5 hydrogens and carbons) but
becomes slow below -90 °C, thus rendering these hydrogens
diastereotopic. Line shape simulation yields a barrier of 10.15
( 0.15 kcal mol-1 (Table 3) for the chair to boat ring
inversion.39
On the contrary, the OMe signal of the minor (3%) form of
2-H+ remains a single line in the same temperature range. This
behavior is in keeping with the structure predicted by DFT
computations for the minor conformer, where the two perhy-
droquinolizine rings are equal (both have the shape of a chair
as in Figure S8 of Supporting Information), thus in this form,
the two aryl rings cannot become diastereotopic.
In the same temperature range, the major form also displays
dynamic effects for each of the aromatic doublet signals of the
hydrogens in the ortho and meta positions to the methoxy
substituents (H12 and H11, respectively). Both signals eventu-
ally split into three doublets with a 1:1:2 intensity ratio (Figure
7), indicating that, in addition to the restricted chair to boat
interconversion, the rotation of one of the two aryl groups is
also restricted at -93 °C whereas the other is not. This dynamic
process is essentially the same as that described above for the
corresponding amine 2.40 Accordingly, the higher rotation barrier
of one aryl group (labeled A in Figure S8 of Supporting
Information) is not measurable because the related effects are
detectable only when the faster ring inversion is also frozen.
On the other hand, the rotation barrier of the second aryl group
(labeled B) must be lower than that for the ring inversion.
Proof of the correctness of this interpretation is offered by
the 13C spectrum (at 150.8 MHz) in CHF2Cl. At about -100 °C,
in fact, the carbons at position 11 display, as do the correspond-
ing CH hydrogens in Figure 7, three signals (one of which is
again twice as intense as the other two), but on further cooling,
the two-fold intense signal broadens significantly and eventually
splits into two 1:1 lines, separated approximately by 500 Hz at
-152 °C. At this temperature, therefore, the rotation of the
second aryl group B is also frozen and the corresponding barrier
(5.5 ( 0.3 kcal mol-1) is lower, as anticipated, than that
measured for the ring inversion. The trend of the computed DFT
The solid-state structure of 2-H+, obtained by single-crystal
X-ray diffraction, is essentially equal to that proposed for the
major form in solution (see Figure S8 of Supporting Informa-
tion), thus confirming that the N-H+ and the H-C9b bonds
are in a synclinal relationship and also that one of the two six-
membered rings is a chair and the other a boat.
(35) The DFT computations were performed, for convenience, on the
free cation without including the presence of the anion CF3COO-. This
might account for the computed energy difference (6 kcal mol-1) being
larger than the ∆G° value (1.9 kcal mol-1), corresponding to the
experimental ratio measured at -10 °C.
(36) This signal appears as a multiplet at 3.6 ppm with J ) 9.2 Hz, due
to the coupling with the two equivalent H7a,H9a hydrogens, and J ) 4.9
Hz, due to the coupling with the NH+ hydrogen. In the minor form, these
J values are quite different (5.0 and 11.7 Hz, respectively).
(37) The vicinal J coupling between H9b and H7a,H9a, measured in the
major form, was found to be larger (9.2 Hz) than that (5.0 Hz) measured
in the minor form of 2-H+.36 According to DFT computations, the
corresponding dihedral angles of the major asymmetric form of Figure S8
(left) of Supporting Information are 6.6 and 31°, respectively; when inserted
in the Karplus equation,20 they yield a J value of 7.0 Hz (resulting from
the average of 8.1 and 5.9 Hz, respectively). The angles of the more
symmetric minor form, as shown in Figure S8 (right) of Supporting
Information, are both equal to 47°, providing a computed J value of 3.6
Hz. The direct DFT computation of these vicinal J couplings (which include
the contribution of the Fermi contact) provides values of 10.6 Hz (average
of 13.0 and 8.2 Hz) for the major and 6.9 Hz for the minor form. By
combining the two theoretical approaches, the computed coupling of the
major form is expected to lie in a 7.0-10.6 Hz range and the minor in a
3.6-6.9 Hz. Thus the major is predicted to have a vicinal J coupling (8.8
( 1.8 Hz) larger than that (5.2 ( 1.7 Hz) of the minor form, in agreement
with the trend of the experimental values of 9.2 and 5.0 Hz, respectively
(Table 1).
(39) This value is larger than that measured in the corresponding amine
2, suggesting that in the ammonium salt the structure is more rigid. This
trend is opposite to that observed for the barriers of ring inversion processes
in the amine 1 and in its ammonium salt 1-H+. The latter, in fact, has a
structure quite different from that of 2-H+, thus making its shape more
flexible than that of the corresponding amine 1.
(40) The line shape simulation of Figure 7 was obtained using the very
same rate constants derived from the simulation of the OMe signal (i.e.,
the rates corresponding to the chair to boat ring inversion). Furthermore,
in order to obtain a good simulation, the rates for the direct exchange
between the two downfield signals with a 1:1 intensity could not be included,
proving that these signals exchange via the intermediacy of the third signal
(that upfield with a double intensity). As discussed in the case of the amine
2, this proves that the observed motion does not allow the measurement of
the rotation barrier but rather the barrier for ring inversion.
(38) Also, the vicinal H-N-C-H couplings between NH+ and H9b
(4.9 and 11.7 Hz for the major and minor form, respectively36) can be
rationalized on the basis of the appropriate Karplus-like equation (Fraser,
R. R.; Renaud, R. N.; Saunders, J. K.; Wigfield, Y. Y. Can. J. Chem. 1973,
51, 2433). The corresponding computed dihedral angles for the major (38.5°)
and the minor (180°) form yield J values of 4.9 and 11.6 Hz, respectively,
and the direct DFT computations predict 6.9 and 12.0 Hz, respectively.
Thus the H-N-C-H coupling of the major is expected to lie in a 4.9-
6.9 Hz range and that of the minor form in a 11.6-12.0 Hz. These values
(i.e., 5.9 ( 1 and 11.8 ( 0.2 Hz, as in Table 1) are again in good agreement
with the experimental data and further support the proposed assignment.
J. Org. Chem, Vol. 73, No. 2, 2008 685

Lunazzi et al.
FIGURE 7. Left: Aromatic spectral region (600 MHz in CD2Cl2) of the ammonium salt 2-H+, where each of the doublet signals of H-11 (red)
and H-12 (blue) splits, at -93 °C, into three 1:1:2 doublets. Right: Line shape simulation obtained with the same rate constants derived from those
of the OMe line in Figure S9 of Supporting Information (see text). Assignment of the signals was obtained by HSQC acquired at -93 °C (see
Figure S10 of Supporting Information).
values for 2-H+ (Table 3) agrees with this interpretation since
the high and low aryl rotation barriers are 16.6 and 7.3 kcal
mol-1, respectively, and the chair to boat ring inversion barrier
has an intermediate value (15.0 kcal mol-1).41
groups displaying a dynamic pseudoequatorial disposition),
whereas in the case of 2, the two six-membered rings adopt the
shape of a chair and of a boat (with the stacked aryl groups
displaying a dynamic pseudoaxial disposition). The barriers for
the ring inversion (8.6 and 7.0 kcal mol-1 for 1 and 2,
respectively) and aryl rotation have been determined by dynamic
NMR spectroscopy, with values in fair agreement with the
theoretical predictions. The corresponding ammonium salts (1-
H+ and 2-H+) exhibit the same type of structure as well as
analogous conformations. The ring inversion barriers were also
determined; in the case of 1-H+, it was found to be lower (7.7
kcal mol-1) than that of its amine 1, whereas in the case of
2-H+, it was found to be higher (10.15 kcal mol-1) than that of
its amine 2. The structures of the two ammonium salts
determined in solution (i.e., the cis,cis ring junction at the
perhydrocyclopentaquinolizine moiety) were also confirmed by
single-crystal X-ray diffraction.
Concluding Remarks
The structures and conformations of the cyclic amines 1 and
2 were determined by means of NOE experiments, analysis of
vicinal J coupling constants, and DFT computations. Both
display a cis,cis junction at the perhydrocyclopentaquinolizine
moiety; in the case of 1, the two six-membered rings adopt the
shape of a chair and of a twisted-boat (with the stacked aryl
(41) The computed barriers of Table 3 are all overestimated, although
their sequence does parallel the experimental trend. The main source of
approximations in these computations is the consequence of not having
considered the presence of the CF3COO- anion (in order to reduce the
computational time), thus treating 1-H+ and 2-H+ as “naked” cations.
686 J. Org. Chem., Vol. 73, No. 2, 2008

Aryl-Substituted Perhydrocyclopentaquinolizines
SCHEME 2
was removed under reduced pressure and the crude mixture
separated by column chromatography (silica gel 100-200 mesh,
hexane/ethyl acetate 90:10 to 80:20) to give 4 (1.34 g, yield )
26%) and 58a (4.92 g, yield ) 58%).
(3S*,5R*,7aR*,9aS*)-3,5-Di(4-methoxyphenyl)perhydrocyclo-
penta[ij]quinolizine (1) and (3R*,5S*,7aR*,9aS*)-3,5-Di(4-meth-
oxyphenyl)perhydrocyclopenta[ij]quinolizine (2). To a stirred
solution of NaBH(OAc)3 (738 mg, 3.67 mmol) in dry THF (10
mL) were added 2-[3-(4-methoxyphenyl)-3-oxopropyl]-5-(3-oxo-
3-phenylpropyl)cyclopentan-1-one 5 (500 mg, 1.22 mmol), am-
monium acetate (471 mg, 6.13 mmol), and acetic acid (0.5 mL), in
sequence, at room temperature under a blanket of dry nitrogen.
The resulting reaction mixture was stirred and placed in a preheated
oil bath at 60 °C for 1 h. The mixture was then cooled to ambient
temperature, and the pH was adjusted to 7.5 with 20% NaOH (about
8 mL). To the resulting biphasic mixture were added dichlo-
romethane (DCM, 20 mL) and water (5 °C, 25 mL), and the organic
layer was separated. The aqueous layer was extracted with
dichloromethane (10 mL × 2). The combined organic layer was
washed with water (2 × 50 mL) and brine (20 mL) and dried over
anhydrous Na2SO4. The solvent was removed under reduced
pressure and the crude mixture subjected to column chromatography
(silica gel 100-200 mesh, hexane/ethyl acetate 97:3 to 90:10) to
obtain 1 and 2 in 80% (369 mg) yield and in a 7:3 ratio.
(3S*,5R*,7aR*,9aS*)-3,5-Di(4-methoxyphenyl)perhydrocyclo-
penta[ij]quinolizine (1): Yield 256 mg (54%); mp (uncorrected)
1
90-93 °C; Rf (97:3 hexane/ethyl acetate) ) 0.52; H NMR (600
MHz, CD2Cl2, 25 °C, TMS) δ 1.51-1.58 (4H, m), 1.65-1.73 (4H,
m), 1.79-1.86 (2H, m), 1.98-2.06 (2H, m), 2.14-2.21 (2H, m),
2.86 (1H, t, J ) 4.5 Hz, H9b), 3.22 (2H, dd, J ) 6.0, 4.6 Hz,
H3,H5), 3.63 (6H, s, OMe), 6.35-6.38 (2H, m), 6.76 (2H, br s);
13C NMR (150.8 MHz, CD2Cl2, 25 °C, TMS) δ 24.7 (CH2), 30.7
(CH2), 31.5 (CH2), 41.6 (CH, C7a and C9a), 55.9 (CH3, OMe),
64.7 (CH, C9b), 67.4 (CH, C3, and C5), 112.8 (CH), 130.2 (CH,
br), 138.8 (q), 158.3 (q); IR (KBr solution) νmax (neat) 3039, 2911,
2765, 1606, 1479, 965, 845, 785 cm-1; HRMS (EI) m/z calcd for
C25H31NO2 377.235479, found 377.2354.
(3R*,5S*,7aR*,9aS*)-3,5-Di(4-methoxyphenyl)perhydrocyclo-
penta[ij]quinolizine (2): Yield 113 mg (26%); mp (uncorrected)
102-105 °C; Rf (97:3 hexane/ethyl acetate) ) 0.40; 1H NMR (600
MHz, CD2Cl2, 25 °C, TMS) δ 1.34-1.42 (2H, m), 1.43-1.50 (2H,
m), 1.58-1.68 (4H, m), 1.74-1.80 (2H, m), 1.91-2.10 (4H, m),
3.31 (1H, t, J ) 8.4 Hz, H9b), 3.73 (6H, s, OMe), 3.87 (2H, t, J )
6.8 Hz, H3,H5), 6.76 (2H, m), 7.28 (2H, m); 13C NMR (150.8 MHz,
CD2Cl2, 25 °C, TMS) δ 27.4 (CH2), 30.0 (CH2), 31.2 (CH2), 39.1
(CH, C7a, and C9a), 55.9 (CH3, OMe), 56.1 (CH, C9b), 60.4 (CH,
C3, and C5), 113.8 (CH), 129.3 (CH), 139.0 (q), 158.9 (q); IR (KBr
solutions) νmax (neat) 2931, 2816, 1483, 1440, 1129, 761, 707
cm-1; HRMS (EI) m/z calcd for C25H31NO2 377.235479, found
377.2355.
(3S*,5R*,7aR*,9aS*)-3,5-Di(4-methoxyphenyl)perhydrocyclo-
penta[ij]quinolizine Trifluoroacetate (1-H+) and (3R*,5S*,7aR*,-
9aS*)-3,5-Di(4-methoxyphenyl)perhydrocyclopenta[ij]quino-
lizine Trifluoroacetate (2-H+). A CF3COOH solution (1 M in
CDCl3) was added to a CDCl3 solution of 1 (20 mg, 0.053 mmol)
directly in the NMR tube. The reaction was followed by acquiring
the NMR spectrum after each addition, monitoring the disappear-
ance of the free base signals. When the conversion was complete,
the solvent was evaporated and the residue purified by crystalliza-
tion (CHCl3). The same procedure was applied in the case of 2.
Crystals suitable for X-ray diffraction were obtained by slow
evaporation of the solvent (CHCl3 in both cases).
(3S*,5R*,7aR*,9aS*)-3,5-Di(4-methoxyphenyl)perhydrocyclo-
penta[ij]quinolizine Trifluoroacetate (1-H+): 1H NMR (600 MHz,
CD2Cl2, -10 °C, TMS) δ 1.60-1.67 (2H, m), 1.83-1.98 (6H, m),
2.26-2.36 (2H, m), 2.45-2.53 (2H, m), 2.72-2.81 (2H, m), 3.47
(1H, dt, J ) 8.7, 4.4 Hz, H9b), 3.61 (6H, s, OMe), 3.79 (2H, ddd,
J ) 10.3, 8.2, 2.9 Hz, H3,H5), 6.34 (4H, br s), 6.54 (2H, br s),
7.57 (2H, br s), 10.04 (1H, br s, NH); 13C NMR (150.8 MHz, CD2-
Experimental Section
Material. The isomeric compounds 1 and 2 were prepared
following the reaction pathway displayed in Scheme 2.
The Mannich base 3, prepared from the corresponding Mannich
salt,42 was condensed with cyclopentanone in polyethyleneglycol-
200 (PEG-200) under microwave irradiation to provide a mixture
of diketone 4 and triketone 5 in a 2.2:1 ratio. The triketone 58a was
obtained as a mixture of cis- and trans-isomers in an 85:15 ratio.
The molecular stitching reductive amination-cyclization of the
triketone 5 was next conducted with ammonium acetate and sodium
triacetoxyborohydride. This reaction provided (3S*,5R*,7aR*,9aS*)-
3,5-di(4-methoxyphenyl)perhydrocyclopenta[ij]quinolizine 1 and
(3R*,5S*,7aR*,9aS*)-3,5-di(4-methoxyphenyl)perhydrocyclopenta-
[ij]quinolizine 2 in a 7:3 ratio (80% overall yield).
2-[3-(4-Methoxyphenyl)-3-oxopropyl]-5-(3-oxo-3-phenylpro-
pyl)cyclopentan-1-one (5). â-Dimethylaminopropiophenone hy-
drochloride (5 g, 20.5mmol) was taken in a beaker, and the
minimum amount of water (10 mL) was added to dissolve the salt.
The beaker was kept in an ice bath, and 20% aqueous sodium
hydroxide was added dropwise, while periodically checking the pH
by means of a pH paper. As neutralization proceeded, the solution
became turbid. The addition of sodium hydroxide was continued
until the pH reached 10, at which point an oily layer of base was
visible. This oily layer was extracted with dichloromethane and
concentrated to give â-dimethylaminopropiophenone 3 (4.2 g, 20.3
mmol), to which were added cyclopentanone (853 mg, 10 mmol),
triethylamine (2.81 mL, 20.28 mmol), and PEG-200 (10 mL) in a
50 mL conical flask. The resulting mixture was irradiated, at
atmospheric pressure, in a domestic microwave oven (BPL-Sanyo,
India; monomode, multi-power; power source: 230 V, 50 Hz,
microwave frequency: 2450 MHz) at 370 W for 2 min. The reaction
mixture was cooled to room temperature, diluted with 60 mL of
dichloromethane, and poured over ice-cooled water; the organic
layer was separated, washed again with water (2 × 50 mL) and
saturated aqueous NaCl (50 mL), and dried (Na2SO4). The solvent
(42) Vogel’s Textbook of Practical Organic Chemistry, 4th ed.; Furnis,
B. S., Hannaford, A. J., Rogers, V., Smith, P. W. G., Tatchell, A. R., Eds.;
ELBS: London, 1978; p 815.
J. Org. Chem, Vol. 73, No. 2, 2008 687

Lunazzi et al.
Cl2, -10 °C, TMS) δ 24.9 (CH2), 27.1 (CH2), 31.6 (CH2), 41.2
(CH, C7a, and C9a), 55.9 (CH3, OMe), 73.0 (CH, C3, and C5),
75.9 (CH, C9b), 114.3 (CH), 130.6 (q), 131.4 (CH, br), 159.7 (q),
MS (ESI+) m/z 378[(M - CF3COO-)+, 100%]; MS(ESI-) m/z
113 [CF3COO-, 100%].
decoupling was achieved with the standard Waltz-16 sequence. A
line broadening function of 1-5 Hz was applied to the FIDs before
Fourier transformation. Usually 512-1024 scans were acquired.
Temperature calibrations were performed immediately before the
experiments, using a Cu/Ni thermocouple immersed in a dummy
sample tube filled with isopentane, and under conditions as nearly
identical as possible. The uncertainty in the temperatures was
estimated from the calibration curve to be (1.0 °C. The line shape
simulations were performed by means of a PC version of the QCPE
program DNMR 6, no. 633, Indiana University, Bloomington, IN.
(3R*,5S*,7aR*,9aS*)-3,5-Di(4-methoxyphenyl)perhydrocyclo-
penta[ij]quinolizine Trifluoroacetate (2-H+): 1H NMR (600 MHz,
CD2Cl2, -10 °C, TMS) δ 1.44-1.57 (4H, m), 1.76 (2H, br s),
2.02-2.15 (4H, m), 2.21-2.32 (2H, m), 2.48 (2H, br s), 3.57 (1H,
dt, J ) 9.2, 4.9 Hz, H9b), 3.63 (minor OMe), 3.77 (6H, s, OMe),
4.17 (2H, br m, H3,H5), 4.43 (minor form, dt, J ) 11.6, 5.0 Hz,
H9b), 4.80 (minor form, br m, H3,H5), 6.41 (minor form, d, J )
8.9 Hz), 6.90 (4H, d, J ) 8.2 Hz), 7.46 (2H, br s), 9.95 (1H, br s,
NH); 13C NMR (150.8 MHz, CD2Cl2, +25 °C, TMS) δ 25.9 (CH2,
br), 26.5 (CH2), 31.0 (CH2), 36.0 (CH, C7a, and C9a), 56.1 (CH3,
OMe), 58.6 (CH, C3, and C5), 63.6 (CH, C9b), 115.1 (CH), 128.4
(q), 130.8 (CH, br), 161.2 (q); MS (ESI+) m/z 378[(M -
CF3COO-)+, 100%]; MS(ESI-) m/z 113 [CF3COO-, 100%].
NMR Spectroscopy. The spectra were recorded at 600 MHz
Calculations. Computations were carried out at the B3LYP/6-
31G(d) level by means of the Gaussian 03 series of programs18
(see Supporting Information); the standard Berny algorithm in
redundant internal coordinates and default criteria of convergence
were employed. The reported energy values are not ZPE corrected.
Harmonic vibrational frequencies were calculated for all of the
stationary points. For each optimized ground state, the frequency
analysis showed the absence of imaginary frequencies, whereas each
transition state showed a single imaginary frequency. Visual
inspection of the corresponding normal mode was used to confirm
that the correct transition state had been found. The J coupling
calculations were obtained at the B3LYP/6-31G(d) level using the
program18 option that includes the Fermi contact contribution.
for 1H and 150.8 MHz for 13C. Full assignments of the 1H and 13
C
signals were obtained by bi-dimensional experiments (g-COSY,
edited-gHSQC,43 and gHMBC44 sequences). The NOE experiments
were obtained by means of the DPFGSE-NOE45 sequence. To
selectively irradiate the desired signal, a 50 Hz wide shaped pulse
was calculated with a refocusing SNOB shape46 and a pulse width
of 37 ms. Mixing time was set to 0.75 ÷ 1.1 s. The samples for
obtaining spectra at temperatures lower than -100 °C were prepared
by connecting to a vacuum line the NMR tubes containing the
compound and a small amount of C6D6 (for locking purpose) and
condensing therein the gaseous CHF2Cl and CHFCl2 (4:1 v/v) under
cooling with liquid nitrogen. The tubes were subsequently sealed
in vacuo and introduced into the precooled probe of the spectrom-
eter. Low-temperature 13C spectra were acquired with a 5 mm dual
probe, without spinning, with a sweep width of 38 000 Hz, a pulse
width of 4.9 µs (70° tip angle), and a delay time of 2.0 s. Proton
Acknowledgment. L.L. and A.M. received financial support
from the University of Bologna (RFO) and from MUR-COFIN
2005, Rome (national project “Stereoselection in Organic
Synthesis”). H.S.P.R. thanks University Grants Commission
(UGC), India, for Special Assistance Program (SAP-DRS), and
Council of Scientific Industrial Research (CSIR), India, and the
Department of Science and Technology, India (DST-FIST), for
financial assistance. S.R. thanks CSIR for the Junior Research
Fellowship in the major research project awarded to H.S.P.R.
We thank Sophisticated Instrumentation Facility (SIF) and
Sophisticated Analytical Instrumentation Center (SAIC) for
generously recording preliminary 400 MHz NMR spectra.
(43) (a) Bradley, S. A.; Krishnamurthy, K. Magn. Reson. Chem. 2005,
43, 117. (b) Willker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W. Magn.
Reson. Chem. 1993, 31, 287.
(44) Hurd, R. E.; John, B. K. J. Magn. Reson. 1991, 91, 648.
(45) (a) Stott, K.; Stonehouse, J.; Keeler, J.; Hwand, T.-L.; Shaka, A. J.
J. Am. Chem. Soc. 1995, 117, 4199. (b) Stott, K.; Keeler, J.; Van, Q. N.;
Shaka, A. J. J. Magn. Reson. 1997, 125, 302. (c) Van, Q. N.; Smith, E. M.;
Shaka, A. J. J. Magn. Reson. 1999, 141, 191. (d) See also: Claridge, T. D.
W. High Resolution NMR Techniques in Organic Chemistry; Pergamon:
Amsterdam, 1999.
Supporting Information Available: Additional variable-tem-
perature spectra, DFT-computed structures, NOE spectra for 1, 2,
1-H+, and 2-H+, X-ray diffraction data for 1-H+ and 2-H+, ambient
temperature 1H, 13C NMR, and selected 2D spectra, computational
data, and J coupling matrix for 1, 2, 1-H+, and 2-H+. This material
is available free of charge via the Internet at http://pubs.acs.org.
(46) Kupcˇe, E.; Boyd, J.; Campbell, I. D. J. Magn. Reson., Ser. B 1995,
106, 300.
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