Two isomers of 2,4-dibenzyl-8-azabicyclo[3.2.1]octan-3-ol

Article abstract of DOI:10.1107/S0108270103026520

The crystal structure of two isomers of 2,4-dibenzyl-8-azabicyclo[3.2.1]octane-3-ol were studied. The molecules were linked together by intermolecular O-H···N hydrogen bonds to form chains. The structures of the compounds were similar with the piperidine

Full text of DOI:10.1107/S0108270103026520

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
for treating central nervous system disorders, we have
designed and synthesized a number of tropane derivatives.
Compounds (I) and (II) are two isomeric tropane derivatives
that we prepared recently. Both (I) and (II) were synthesized
stereospeci®cally and identi®ed initially by MS and NMR
spectroscopy. In order to con®rm unequivocally the stereo-
chemistry of these compounds, and to gather more informa-
tion on the structural conformation of the molecules for our
molecular recognition studies, the crystal structures of (I) and
(II) have been determined.
The molecular structures of (I) and (II) are shown in Fig. 1,
while selected geometric parameters are presented in Tables 1
and 2. As expected, the structures of (I) and (II) are similar,
with the piperidine ring in a chair conformation, the pyrroli-
dine ring in an envelope conformation with atom N as the ¯ap,
and the benzyl groups and the bridgehead N-methyl group
bonded equatorially to the piperidine ring. However, in (I),
the hydroxy group is attached axially to the piperidine ring on
atom C3, whereas in (II), the hydroxy group is attached
equatorially to the piperidine ring on atom C3. In (I), because
of the steric interactions between the hydroxy group and the
benzyl groups, the C2 and C4 benzyl groups are not mirror
symmetric, as indicated by the unequal torsion angles around
the C2ÐC9 and C9ÐC10 bonds and around the C4ÐC16 and
ISSN 0108-2701
Two isomers of 2,4-dibenzyl-8-aza-
bicyclo[3.2.1]octan-3-ol
Guangrong Zheng,a Sean Parkin,b Linda P. Dwoskina and
Peter A. Crooksa*
aDepartment of Pharmaceutical Sciences, College of Pharmacy, University of
Kentucky, Lexington, KY 40536, USA, and bDepartment of Chemistry, University
of Kentucky, Lexington, KY 40536, USA
Correspondence e-mail: pcrooks@uky.edu
Received 23 October 2003
Accepted 18 November 2003
Online 6 December 2003
The crystal structures of the title compounds, 2ꢀ,4ꢀ-dibenz-
yl-3ꢀ-tropanol (2ꢀ,4ꢀ-dibenzyl-8-methyl-8-azabicyclo[3.2.1]-
octan-3ꢀ-ol), C22H27NO, (I), and 2ꢀ,4ꢀ-dibenzyl-3ꢁ-tropanol
(2ꢀ,4ꢀ-dibenzyl-8-methyl-8-azabicyclo[3.2.1]octan-3ꢁ-ol),
C22H27NO, (II), show that both compounds have a piperidine
ring in a chair conformation and a pyrrolidine ring in an
envelope conformation. Isomer (I) is asymmetric, the benzyl
groups having different orientations, whereas isomer (II) is
mirror symmetric, and the N and O atoms, the C atom
attached to the hydroxy group, and the methyl C atom
attached to the N atom lie on the mirror plane. In the crystal
structures of both (I) and (II), the molecules are linked
together by intermolecular OÐHÁ Á ÁN hydrogen bonds to
form chains that run parallel to the a direction in (I) and
parallel to b in (II).
Comment
The tropane ring system is present in the natural product
cocaine and in a number of other compounds that display
interesting pharmacological properties. Numerous novel
tropane analogs have been synthesized and evaluated as
inhibitors of dopamine, serotonin and norepinephrine trans-
porters in an effort to probe the topology of the cocaine
binding site on these biogenic amine transporters (Carrol et
al., 1999; Newman, 2000; Cappelli et al., 2002; Newman &
Kulkarni, 2002). In efforts to develop novel therapeutic agents
Figure 1
A view of the molecules of (a) isomer (I) and (b) isomer (II).
Displacement ellipsoids are drawn at the 50% probability level.
Acta Cryst. (2004). C60, o9±o11
DOI: 10.1107/S0108270103026520
# 2004 International Union of Crystallography o9

organic compounds
C16ÐC17 bonds (Table 1). This conformation probably
results from a repulsive interaction between the H atoms on
atom C16 and the hydroxy group on atom C3, which causes
the exocyclic OÐC3ÐC4 angle [112.36 (16)ꢁ] to be slightly
larger than the OÐC3ÐC2 angle [109.51 (15)ꢁ]. In addition to
the asymmetric phenyl rings in (I), the tropane ring system
itself is also slightly contorted, as evidenced by the endocyclic
bond lengths and angles (Table 1). The C1ÐC2 and C9ÐC10
bonds in (I) are approximately coplanar [C1ÐC2ÐC9Ð
C10 = 176.53 (18)ꢁ]. In (II), where there is less intramole-
cular crowding, the whole molecule is mirror symmetric, with
atoms N, O, C3 and C8 lying on the mirror plane (Table 2). In
contrast to (I), the C2ÐC3 and C9ÐC10 bonds in (II) are
approximately coplanar, as evidenced by the C3ÐC2ÐC9Ð
C10 torsion angle [173.7 (2)ꢁ].
structure of (II), parallel intermolecular OÐHÁ Á ÁN hydrogen
1
Ê
bonds [symmetry code: x, y + 1, z 2; HÁ Á ÁN = 2.07 A,
ꢁ
Ê
OÁ Á ÁN = 2.846 (3) A and OÐHÁ Á ÁN = 154 ] link the mol-
ecules into an in®nite one-dimensional linear array, which is
parallel to the b axis (Fig. 3).
Experimental
2(E),4(E)-Dibenzylidenetropanone (Jung et al., 2001) was reduced
stereoselectively to 2ꢀ,4ꢀ-dibenzyltropanone by catalytic hydro-
genation (45 psi H2) over Pd/C (10%) in absolute methanol. Using
diisobutylaluminium hydride at 195 K in tetrahydrofuran, 2ꢀ,4ꢀ-di-
benzyltropanone was then reduced stereoselectively to (I), which was
puri®ed by ¯ash column chromatography on silica gel and then
recrystallized from acetonitrile (m.p. 489 K). 1H NMR (300 MHz,
CDCl3): ꢂ 7.13±7.32 (m, 10H), 3.56 (m, 1H), 2.79 (m, 2H), 2.61±2.78
(m, 4H), 2.19 (s, 3H), 2.10±2.23 (m, 4H), 1.83 (m, 2H), 1.29 (d,
J = 5.4 Hz, 1H, OH); 13C NMR (75 MHz, CDCl3): ꢂ 140.48, 129.17,
128.52, 126.03, 69.08, 64.03, 47.39, 40.89, 35.72, 22.00. Compound (II)
was prepared stereoselectively by reduction of 2ꢀ,4ꢀ-dibenzyl-
tropanone with Zn/Hg in 20% HCl/1,4-dioxane (1:1) under re¯ux.
Crude (II) was puri®ed by the same method as used for (I) (m.p.
508 K). 1H NMR (300 MHz, CDCl3): ꢂ 7.12±7.22 (m, 10 H), 3.10±3.22
(m, 3H), 2.80 (m, 2H), 2.33 (dd, J = 13.5, 10.2 Hz, 2H), 2.12 (s, 3H),
2.01 (m, 2H), 1.86 (m, 2H), 1.68 (m, 2H); 13C NMR (75 MHz, CDCl3):
ꢂ 140.45, 129.18, 128.59, 126.10, 74.39, 63.65, 50.97, 40.25, 36.56, 22.02.
Crystals of (I) and (II) suitable for X-ray diffraction studies were
obtained by slow evaporation of acetonitrile solutions at room
temperature. X-ray data were collected from ¯ash-cooled crystals.
Crystals of (I) were observed to shatter upon cooling below ꢂ200 K,
so for this crystal, data were collected at 206 K.
The molecules of (I) form in®nite chains along the a axis
(Fig. 2), and the molecules in these chains are connected by a
zigzag pattern of intermolecular OÐHÁ Á ÁN hydrogen bonds
1
2
Ê
[symmetry code:
x
,
y + 12,
z; ꢁ HÁ Á ÁN = 1.96 A,
Ê
OÁ Á ÁN = 2.793 (2) A and OÐHÁ Á ÁN = 170 ]. In the crystal
Isomer (I)
Crystal data
C22H27NO
Mr = 321.45
Orthorhombic, P212121
Ê
a = 10.4244 (4) A
Mo Kꢀ radiation
Cell parameters from 11 302
re¯ections
ꢃ = 1.0±27.5ꢁ
1
Ê
Figure 2
The crystal packing of (I), viewed along the b axis. Intermolecular
hydrogen bonds are shown as dashed lines.
b = 11.4988 (5) A
ꢄ = 0.07 mm
T = 206 (1) K
Ê
c = 15.1602 (5) A
3
Ê
V = 1817.22 (12) A
Block, colorless
0.24 Â 0.24 Â 0.20 mm
Z = 4
Dx = 1.175 Mg m
3
Data collection
Nonius KappaCCD diffractometer
! scans at ®xed ꢅ = 55ꢁ
Rint = 0.066
ꢃmax = 27.5ꢁ
14 506 measured re¯ections
2371 independent re¯ections
1902 re¯ections with I > 2ꢆ(I)
h = 13 ! 13
k = 14 ! 14
l = 19 ! 19
Table 1
Selected geometric parameters (A, ) for (I).
ꢁ
Ê
NÐC5
NÐC1
C2ÐC3
1.486 (2)
1.488 (2)
1.530 (3)
C2ÐC9
C3ÐC4
C4ÐC16
1.531 (3)
1.539 (3)
1.527 (3)
NÐC1ÐC2
C3ÐC2ÐC9
OÐC3ÐC2
106.88 (15)
112.98 (15)
109.51 (15)
OÐC3ÐC4
C16ÐC4ÐC3
NÐC5ÐC4
112.36 (16)
112.27 (15)
107.22 (15)
C3ÐC2ÐC9ÐC10
C1ÐC2ÐC9ÐC10
C2ÐC9ÐC10ÐC15
55.7 (2)
176.53 (18)
58.9 (3)
C3ÐC4ÐC16ÐC17
C4ÐC16ÐC17ÐC18
157.74 (18)
61.0 (3)
Figure 3
The crystal packing of (II), viewed along the a axis. Intermolecular
hydrogen bonds are shown as dashed lines.
ꢀ
o10 Guangrong Zheng et al.
C22H27NO and C22H27NO
Acta Cryst. (2004). C60, o9±o11

organic compounds
Re®nement
Table 2
Selected geometric parameters (A, ) for (II).
ꢁ
Ê
Re®nement on F2
R[F2 > 2ꢆ(F2)] = 0.043
wR(F2) = 0.096
S = 1.44
2371 re¯ections
219 parameters
(Á/ꢆ)max = 0.005
Áꢇmax = 0.18 e A
3
Ê
3
NÐC1
NÐC1i
1.485 (3)
1.486 (3)
C2ÐC3
C3ÐC2i
1.531 (3)
1.531 (3)
Ê
0.17 e A
Extinction correction: SHELXL97
Áꢇmin
=
Extinction coef®cient: 0.0126 (17)
OÐC3ÐC2
108.83 (16)
OÐC3ÐC2i
108.83 (16)
61.6 (3)
H-atom parameters constrained
w = 1/[ꢆ2(F2o) + (0.0496P)2
+ 0.0877P]
where P = (F2o + 2Fc2)/3
C9ÐC2ÐC3ÐO
C3ÐC2ÐC9ÐC10
73.4 (3)
173.7 (2)
C1ÐC2ÐC9ÐC10
Symmetry code: (i) x; y; z.
Isomer (II)
For both compounds, data collection: COLLECT (Nonius, 1998);
cell re®nement: SCALEPACK (Otwinowski & Minor, 1997); data
reduction: DENZO±SMN (Otwinowski & Minor, 1997); program(s)
used to solve structure: SHELXS97 (Sheldrick, 1997); program(s)
used to re®ne structure: SHELXL97 (Sheldrick, 1997); molecular
graphics: XP in SHELXTL/PC (Sheldrick, 1995); software used to
prepare material for publication: SHELX97-2 (Sheldrick, 1997) and
local procedures.
Crystal data
C22H27NO
Mr = 321.45
Mo Kꢀ radiation
Cell parameters from 4871
re¯ections
Orthorhombic, Cmc21
Ê
a = 17.8580 (8) A
ꢃ = 1.0±27.5ꢁ
1
Ê
b = 10.5480 (9) A
ꢄ = 0.07 mm
T = 173 (1) K
Ê
c = 9.2364 (8) A
Ê
V = 1739.8 (2) A
Z = 4
Dx = 1.227 Mg m
3
Needle, colorless
0.50 Â 0.10 Â 0.08 mm
3
This research was supported by the National Institute of
Health (grant Nos. DA13519 and DA00399).
Data collection
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SQ1138). Services for accessing these data are
described at the back of the journal.
Nonius KappaCCD diffractometer
! scans at ®xed ꢅ = 55ꢁ
5089 measured re¯ections
1085 independent re¯ections
861 re¯ections with I > 2ꢆ(I)
Rint = 0.075
max = 27.4ꢁ
h = 23 ! 22
k = 13 ! 13
l = 11 ! 8
ꢃ
References
Re®nement
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3
Ê
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Extinction coef®cient: 0.0042 (10)
For both structures, Friedel pairs were merged prior to the ®nal
re®nement cycles because values of the Flack (1983) parameters
(obtained in each case as a variable in the full-matrix least-squares
scheme against unmerged data) re®ned to values with no physical
interpretation.
ꢀ
Acta Cryst. (2004). C60, o9±o11
Guangrong Zheng et al.
C22H27NO and C22H27NO o11