Optically active diaryl tetrahydro-isoquinoline derivatives

Article abstract of DOI:10.1107/S0108270110053357

In (1R,3S)-6,7-dimeth-oxy-3-(meth-oxy-diphenyl-methyl)-1-phenyl-1,2,3,4- tetra-hydro-isoquinoline, C₃₁H₃₁NO₃, (I), and (1R,3S)-2-benzyl-3-[diphenyl(trimethyl-siloxy)methyl]-6,7-dimeth-oxy-1-phenyl-1, 2,3,4-tetra-hydro-isoq

Full text of DOI:10.1107/S0108270110053357

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
Derived from commercially available l-DOPA, the absolute
stereochemistry of (I) and (II) was confirmed to be R and S at
the C1 and C9 positions by 1H NMR, as shown in Figs. 1 and 2,
respectively.
ISSN 0108-2701
Optically active diaryl tetrahydro-
isoquinoline derivatives
Tricia Naicker,a Thavendran Govender,a Hendrik G.
Krugerb and Glenn E. M. Maguireb*
aSchool of Pharmacy and Pharmacology, University of KwaZulu Natal, Durban
4000, South Africa, and bSchool of Chemistry, University of KwaZulu Natal, Durban
4000, South Africa
Correspondence e-mail: maguireg@ukzn.ac.za
Received 23 October 2010
Accepted 20 December 2010
Online 8 February 2011
In (1R,3S)-6,7-dimethoxy-3-(methoxydiphenylmethyl)-1-phenyl-
1,2,3,4-tetrahydroisoquinoline, C31H31NO3, (I), and (1R,3S)-
2-benzyl-3-[diphenyl(trimethylsiloxy)methyl]-6,7-dimethoxy-
1-phenyl-1,2,3,4-tetrahydroisoquinoline, C40H43NO3Si, (II),
the absolute configurations have been confirmed to be R
and S at the isoquinoline 1- and 3-positions, respectively, by
NMR spectroscopy experiments. Both structures have mono-
clinic (P21) symmetry and the N-containing six-membered
ring assumes a half-chair conformation. The asymmetric unit
of (I) contains one molecule, while (II) has two molecules
within the asymmetric unit. These structures are of interest
with respect to the conformation around the exocyclic C—C
bond: (I) displays an ap (antiperiplanar) conformation, while
(II) displays an sc-exo (synclinal) conformation around this
bond. These conformations are significant for stereocontrol
when these compounds are used as catalysts. Various C—
Hꢀ ꢀ ꢀꢀ and C—Hꢀ ꢀ ꢀO bonds link the molecules together in the
crystal structure of (I). In the crystal structure of (II), three
intermolecular C—Hꢀ ꢀ ꢀꢀ hydrogen bonds help to establish
the packing.
Both structures have monoclinic (P21) symmetry. Com-
pound (I) has a single molecule in the asymmetric unit, while
(II) has two molecules within the asymmetric unit. Molecule
(I) has a methyl group at the O3 position, whilst (II) has a
trimethylsilyl group in this position. In addition, (II) has a
benzyl group on the N atom.
In the structure of (I), intermolecular C—Hꢀ ꢀ ꢀꢀ and C—
Hꢀ ꢀ ꢀO interactions involving atoms O1 and O2 link the mol-
ecules into extended chains which run parallel to the b axis
(Table 1 and Fig. 3). In the chain, the molecules are arranged
so that their tails, linked by the C—Hꢀ ꢀ ꢀO interactions, point
towards the core of the chain and their heads protrude to the
outer edges of the chain, with adjacent molecules alternating
from side-to-side. The C—Hꢀ ꢀ ꢀꢀ interactions link the heads of
those molecules lying on the same side of the chain core.
Comment
The tetrahydroisoquinoline (TIQ) molecule and its deriva-
tives have been widely investigated due to their biological and
pharmaceutical properties. Given our recent success with
TIQ-based ligands for catalytic asymmetric transfer hydro-
genation of prochiral ketones, Henry reactions and hydro-
genation of olefins (Peters et al., 2010). We decided to
investigate the potential of TIQ derivatives as organocatalysts.
Compound (I) has recently been synthesized and evaluated as
a novel iminium-activated organocatalyst in an asymmetric
Diels–Alder reaction (Naicker, Petzold et al., 2010). Com-
pound (II) is novel and is the precursor to the same class of
organocatalysts based on a (1R,3S)-6,7-dimethoxy-1-phenyl-
1,2,3,4-tetrahydroisoquinoline backbone.
Figure 1
The molecular structure of (I), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms have been omitted for clarity.
o100 # 2011 International Union of Crystallography
doi:10.1107/S0108270110053357
Acta Cryst. (2011). C67, o100–o103

organic compounds
Figure 3
A partial projection of the structure of (I), viewed along [010]. Dashed
lines indicate intermolecular interactions. H atoms not involved in
intermolecular interactions have been omitted for clarity.
Figure 2
The molecular structure of (II), showing the atom-numbering scheme.
There are two molecules in the asymmetric unit, labelled with suffixes A
and B. Displacement ellipsoids are drawn at the 50% probability level. H
atoms and some atom labels have been omitted for clarity.
In the structure of (II), each independent molecule displays
an intramolecular C—Hꢀ ꢀ ꢀꢀ interaction, while a single inter-
molecular C—Hꢀ ꢀ ꢀꢀ interaction involving C35A—H links just
the two independent molecules (Table 2). An extended
network of interactions is not present. The crystal packing of
(II) reveals that the pseudosymmetry relates the two inde-
pendent molecules within the asymmetric unit resulting in a
layered packing along the a axis (Fig. 4).
From the crystal structures, it is evident that the
N-containing six-membered rings assume half-chair confor-
mations (Figs. 1 and 2). This result differs from two analogous
compounds, namely (1R,3S)-methyl 2-benzyl-6,7-dimethoxy-
1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate and
(1R,3S)-methyl 6,7-dimethoxy-1-(4-methoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate, which assume half-boat
conformations (Naicker et al., 2009; Naicker, Govender et al.,
2010a). The current study confirms our previous postulation
that the change in conformation is a result of the introduction
of the phenyl groups at the C1 position.
According to the Cambridge Structural Database (Version
5.31; Allen, 2002), the only other crystal structure of a tetra-
hydroisoquinoline derivative with diaryl substitution at the
C10 position is compound (III) (see Scheme), which we
reported recently (Naicker, Govender et al., 2010b). In this
crystal structure, the methanol O atom is a free OH group.
Due to the lack of analogous structures, these diaryl tetra-
hydroisoquinoline alcohols were compared with proline diaryl
Figure 4
A partial projection of the structure of (II), viewed along [100]. The top
and bottom layers contain only B molecules, while the central layer
contains A molecules. Dashed lines indicate intermolecular interactions.
H atoms not involved in intermolecular interactions have been omitted
for clarity.
alcohols (Seebach et al., 2008). Compound (III) displays a
similar conformation to its proline analogue, which displays a
gauche or sc-endo (synclinal) conformation around the O3—
C10—C9—N1 bond, with the OH group partially covering the
piperidine ring with a torsion angle of ꢁ77.0 (2)ꢂ.
Compound (I) displays an ap (antiperiplanar) conformation
around the exocyclic C9—C10 bond, with an O3—C10—C9—
N1 torsion angle of 171.5 (1)ꢂ. This conformation has only
been found in a few examples of N-amino prolinol methyl
esters (Seebach et al., 2008).
Proline diphenyl OTMS (OTMS is trimethylsiloxy) analo-
gues exhibit an sc-exo conformation around the exocyclic
ethane bond, with a torsion angle of 61.0ꢂ. Both molecules of
(II) (Fig. 2) display an sc-endo conformation, with torsion
angles of ꢁ81.1 (3) and ꢁ84.8 (2)ꢂ. A possible reason for this
ꢃ
Acta Cryst. (2011). C67, o100–o103
Naicker et al. C31H31NO3 and C40H43NO3Si o101

organic compounds
(m, 14H), 6.84 (m, 5H), 6.63 (m, 2H), 6.36 (s, 1H), 4.57 (s, 1H), 4.38 (d,
J = 13.63 Hz, 1H), 4.24 (dd, J = 3.38 and 12.13 Hz, 1H), 4.00 (s, 3H),
3.73 (s, 3H), 3.39 (dd, J = 4.32 and 12.58 Hz, 1H), 3.31 (d, J = 13.85 Hz,
1H), 2.29 (dd, J = 3.38 and 16.88 Hz, 1H), 0.0 (s, 9H).
change could be that the benzyl group on the N atom forces
the phenyl rings at the C10 atom to be the furthest away from
it, hence adopting the sc-endo conformation.
Proline diaryl alcohols have been used as successful chiral
catalysts by exploiting the same rotation along the C9—C10
bond (Diner et al., 2008). This change, which is brought about
by different groups on the methanol O atom, makes the
current study particularly useful. This feature is found in (I)
which, when tested for its catalytic activity in the Diels–Alder
reaction, showed poor yields. The structural data demon-
strated how we could improve the catalytic reactivity by
reducing the steric bulk of the ligand. A successful catalyst was
obtained by removing the phenyl moieties from (I) (Naicker,
Petzold et al., 2010).
Compound (I)
Crystal data
3
˚
C31H31NO3
V = 1226.7 (3) A
Z = 2
Mr = 465.57
Monoclinic, P21
a = 11.4071 (14) A
b = 6.4750 (8) A
c = 16.961 (2) A
ꢄ = 101.707 (2)ꢂ
Mo Kꢁ radiation
ꢅ = 0.08 mmꢁ1
T = 173 K
0.22 ꢄ 0.14 ꢄ 0.09 mm
˚
˚
˚
Data collection
Experimental
Bruker APEXII DUO
diffractometer
Absorption correction: multi-scan
(SADABS; Sheldrick, 2008)
Tmin = 0.645, Tmax = 0.746
11498 measured reflections
3737 independent reflections
3191 reflections with I > 2ꢆ(I)
Rint = 0.051
To (1R,3S)-2-benzyl-3-(1,1-diphenylethyl)-6,7-dimethoxy-1-phenyl-
1,2,3,4-tetrahydroisoquinoline (0.4 g, 0.72 mmol), derived from
l-DOPA (Naicker, Petzold et al., 2010), in MeOH–THF (1:1 v/v,
20 ml) was added half an equivalent by mass of 10% palladium on
carbon Pd/C under hydrogen (approximately 1 atm). The reaction
was stirred for 2 h. The crude product was obtained by filtering the
Pd/C through a plug of Celite and the filtrate was then concentrated
to dryness. The resulting residue was purified by column chromato-
graphy (50:50 EtOAc–hexane, RF = 0.6) to yield (I) as a white solid
[yield 0.2 g, 60%; m.p. 463–465 K; [ꢁ]2D0 ꢁ10.0 (c 0.11 in CHCl3)].
Recrystallization from ethyl acetate afforded colourless crystals
suitable for X-ray analysis. IR (neat, ꢂmax, cmꢁ1): 2934, 1514, 1448,
Refinement
R[F2 > 2ꢆ(F2)] = 0.043
wR(F2) = 0.108
S = 1.05
3737 reflections
320 parameters
2 restraints
H atoms treated by a mixture of
independent and constrained
refinement
ꢁ3
˚
Áꢇmax = 0.23 e A
ꢁ3
˚
Áꢇmin = ꢁ0.23 e A
1
1244, 1224, 1063, 698; H NMR (400 MHz, CDCl3, ꢃ, p.p.m.): 7.47–
7.12 (m, 12H), 7.08 (t, J = 7.6 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 6.65 (s,
1H), 6.40 (s, 1H), 5.23 (s, 1H), 3.95 (dd, J = 11.5 and 3.6 Hz, 1H), 3.86
(s, 3H), 3.70 (s, 3H), 2.92–2.75 (m, 4H), 2.52 (dd, J = 16.2 and 11.5 Hz,
3H).
Compound (II)
Crystal data
3
˚
V = 3350 (5) A
Z = 4
C40H43NO3Si
Mr = 613.84
Monoclinic, P21
a = 11.045 (10) A
b = 17.008 (15) A
To a stirred solution of [(1R,3S)-3-(hydroxydiphenylmethyl)-6,7-
dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinolin-2-yl](phenyl)-
methanone (0.6 g, 1.1 mmol), derived from l-DOPA (Naicker,
Petzold et al., 2010), in dry dichloromethane (20 ml) and triethyl-
amine (0.18 ml, 1.3 mmol), trimethylsilyl trifluoromethanesulfonate
(0.24 ml, 1.33 mmol) was added dropwise at 273 K under an inert
atmosphere. The mixture was allowed to warm to room temperature
and was stirred overnight. The mixture was washed with water, the
organic extracts were combined and dried over anhydrous Na2SO4,
and the solvent was removed in vacuo. The resulting residue was
Mo Kꢁ radiation
ꢅ = 0.11 mmꢁ1
T = 100 K
0.22 ꢄ 0.12 ꢄ 0.10 mm
˚
˚
˚
c = 18.489 (15) A
ꢄ = 105.287 (15)ꢂ
Data collection
Bruker APEXII DUO
diffractometer
Absorption correction: multi-scan
(SADABS; Sheldrick, 2008)
Tmin = 0.976, Tmax = 0.989
37993 measured reflections
17263 independent reflections
11255 reflections with I > 2ꢆ(I)
Rint = 0.064
purified by column chromatography (20:80 EtOAc–hexane, RF
=
0.55) to afford (II) as a white solid [yield 0.5 g, 75%; m.p. 458–460 K;
[ꢁ]2D057.58 (c 0.33 in CHCl3)]. Recrystallization from acetone afforded
colourless crystals suitable for X-ray analysis. IR (neat, ꢂmax, cmꢁ1):
2956, 1513, 1245, 839, 696; 1H NMR (400 MHz, CDCl3, ꢃ, p.p.m.): 7.17
Refinement
R[F2 > 2ꢆ(F2)] = 0.057
wR(F2) = 0.124
S = 0.99
17263 reflections
812 parameters
1 restraint
H-atom parameteꢁrs3 constrained
˚
Áꢇmax = 0.38 e A
ꢁ3
˚
Áꢇmin = ꢁ0.41 e A
Absolute structure: Flack (1983)
Flack parameter: 0.00 (10), 8119
Friedel pairs
Table 1
Hydrogen-bond geometry (A, ) for (I).
ꢂ
˚
Cg is the centroid of the C18–C23 ring.
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
Atom H1N on N1 of (I) was located in a difference electron-
density map and refined isotropically with a simple bond-length
˚
restraint of N1—H1N = 0.96 (1) A. All remaining H atoms were
positioned geometrically, with C—H = 0.95 (aromatic), 0.98 (methyl),
C11—H11Aꢀ ꢀ ꢀCgi
C30—H30Aꢀ ꢀ ꢀO1ii
C30—H30Aꢀ ꢀ ꢀO2ii
0.98
0.98
0.98
2.57
2.54
2.59
3.45 (2)
3.356 (2)
3.400 (2)
150
140
140
˚
0.99 (methylene) or 1.00 A (methine), and refined as riding on their
1
2
Symmetry codes: (i) x; y þ 1; z; (ii) ꢁx; y ꢁ ; ꢁz þ 1.
ꢃ
o102 Naicker et al. C31H31NO3 and C40H43NO3Si
Acta Cryst. (2011). C67, o100–o103

organic compounds
Table 2
Hydrogen-bond geometry (A, ) for (II).
The authors thank Dr Hong Su of the Chemistry Depart-
ment of the University of Cape Town for her assistance with
the crystallographic data collection.
ꢂ
˚
Cg1, Cg2, Cg3 and the centroids of the C26B–C31B, C32A–C37A and
C32B–C37B rings, respectively.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SF3143). Services for accessing these data are
described at the back of the journal.
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
C35A—H35Aꢀ ꢀ ꢀCg1i
C40A—H40Aꢀ ꢀ ꢀCg2
C40B—H40Dꢀ ꢀ ꢀCg3
0.95
0.98
0.98
2.80
2.71
2.64
3.669 (3)
3.540 (3)
3.449 (4)
152
143
140
References
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parent atoms, with Uiso(H) = 1.5Ueq(C) for methyl groups or
1.2Ueq(C) otherwise. For (I), the Flack x parameter (Flack, 1983)
based on refinement with 3080 Friedel pairs was ꢁ0.5 (10), which
indicated that no conclusions can be drawn regarding the absolute
structure. Consequently, the Friedel pairs were merged before the
final refinement. For (II), the Flack parameter refined to 0.00 (10)
using 8119 Friedel pairs, which indicated that the refined model
represents the true absolute configuration and is in accordance with
expectation from the known chirality of the starting material in the
synthesis.
For both compounds, data collection: APEX2 (Bruker, 2006); cell
refinement: SAINT (Bruker, 2006); data reduction: SAINT;
program(s) used to solve structure: SHELXS97 (Sheldrick, 2008);
program(s) used to refine structure: SHELXL97 (Sheldrick, 2008);
molecular graphics: OLEX2 (Dolomanov et al., 2009); software used
to prepare material for publication: SHELXL97.
ꢃ
Acta Cryst. (2011). C67, o100–o103
Naicker et al. C31H31NO3 and C40H43NO3Si o103