Stereochemical Features of the condensation of lithiated (S)-N,N-dimethyl-1-phenylethylamine with o-methoxybenzophenones

Article abstract of DOI:10.1007/s11178-005-0203-1

The condensation of lithiated (S)-N,N-dimethyl-1-phenylethylamine with o-methoxybenzophenones occurs in a nonstereoselective fashion due to possible coordination of lithium not only at the carbonyl group but also at the oxygen atom of the ortho-methoxy gr

Full text of DOI:10.1007/s11178-005-0203-1

Russian Journal of Organic Chemistry, Vol. 41, No. 4, 2005, pp. 556–559. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 4, 2005,
pp. 567–570.
Original Russian Text Copyright © 2005 by Dem’yanovich, Shishkina, Gritsyuk, Potekhin, Chesnova, Ashkinadze.
Stereochemical Features of the Condensation
of Lithiated (S)-N,N-Dimethyl-1-phenylethylamine
with o-Methoxybenzophenones
V. M. Dem’yanovich1, I. N. Shishkina1, Ya. A. Gritsyuk1, K. A. Potekhin2,
A. V. Chesnova2, and L. D. Ashkinadze1
1 Faculty of Chemistry, Lomonosov Moscow State University, Vorob’evy gory 1, Moscow, 119899 Russia
e-mail: demyan@org.chem.msu.ru
2 Vladimir State Pedagogical University, Vladimir, Russia
Received July 5, 2004
Abstract—The condensation of lithiated (S)-N,N-dimethyl-1-phenylethylamine with o-methoxybenzophenones
occurs in a nonstereoselective fashion due to possible coordination of lithium not only at the carbonyl group
but also at the oxygen atom of the ortho-methoxy group.
Lithiation of N,N-dialkylbenzylamines is known to
involve the ortho position, leading to o,o'-disubstituted
benzenes which cannot be obtained by other methods
[1]. Lithiation of optically active N,N-dimethyl-1-
phenylethylamine (I) at the ortho position, followed by
condensation with carbonyl compounds, opens the
way to chiral δ-amino alcohols; these compounds are
promising difunctional reagents which, unlike β- and
γ-amino analogs [2], have been studied poorly.
δ-Amino alcohols attract interest as chiral ligands for
asymmetric synthesis [3] and initial compounds for the
preparation of chiral heterocycles [4].
three methyl groups in the ortho and para positions
of benzophenone [6] makes the condensation highly
stereoselective. We also found [6] that the high
diastereoselectivity in the condensation of lithium
derivative II with di- and trimethyl-substituted benzo-
phenones is determined by joint action of steric (the
presence of a methyl group in the ortho position) and
electronic factors (positive inductive effect of the two
methyl groups in positions 2 and 4, regardless of
whether they are located in the same or different
rings). The importance of electronic factor is con-
firmed by 100% diastereoselectivity in the reaction of
II with 3,4-dimethoxybenzophenone [7].
We previously showed that the stereochemical
result of the condensation of lithiated amine I (lithium
derivative II) with unsymmetrical ketones strongly
depends on the structure of the latter and that both
steric and electronic factors of the carbonyl component
are significant. The presence of a bulky alkyl group,
e.g., tert-butyl, in alkyl phenyl ketone [5] or of two or
In the present work we examined reactions of
lithiated amine II with 2-methoxybenzophenone and
a number of dimethoxybenzophenones ArCOAr', anal-
ogs of 2,4-di-, 2,5-di-, and 2,4,6-trimethylbenzophe-
nones which are known to react with II with high
diastereoselectivity [6] to give the corresponding
H
Me
H
Me
H
Me
(S)
(S)
NMe2
OH
NMe2
OH
(S)
(1) BuLi; (2) ArCOAr'
NMe2
+
R
R'
R'
III–VIII
R
I
III, R = H, R' = 2,4-(MeO)2; IV, R = H, R' = 2,5-(MeO)2; V, R = H, R' = 2,6-(MeO)2; VI, R = H, R' = 2-MeO;
VII, R = H, R' = 2-MeO-4,6-Me2; VIII, R = 2-Me, R' = 4-MeO.
1070-4280/05/4104-0556 © 2005 Pleiades Publishing, Inc.

STEREOCHEMICAL FEATURES OF THE CONDENSATION
557
C25
δ-amino alcohols having (S)-configuration of the new
chiral (carbinol) center. The presence of a methoxy
group in the ortho position implies increased number
of potential coordination centers in the resulting amino
alcohols which can be used as ligands for chiral com-
plexes in asymmetric syntheses. In addition, methoxy
groups could affect biological activity of amino alco-
hols; it is known that many biologically active sub-
stances contain a methoxy group which increases their
lipophilicity.
O3
C10
C11
N1
H1
O1
C17
C16
C8
C23
C15
C1
C12
H8
C2
C9
C4
C5
C18
C22
C13
C3
C6
C14
C7
C19
The condensation of lithiated amine II with
methoxy-substituted benzophenones was performed
according to the procedure described previously [5–7],
in a diethyl ether–hexane mixture at –70 and 20°C
under argon. As a result, δ-amino alcohols III–VIII
were obtained; their structure was proved by the IR
and 1H NMR spectra. The hydroxy group in the triaryl-
methanol fragment gives rise to IR absorption at 3200–
C21
O2
C20
C24
Structure of the molecule of (R,R)-2,5-dimethoxyphenyl-
[o-(1-dimethylaminoethyl)phenyl]phenylmethanol (R,R)-(IV)
according to the X-ray diffraction data.
1
2400 cm–1, and the H NMR spectra contain signals
from the methoxy protons at δ 3–4 ppm and hydroxy
proton at δ 9–10 ppm. The position and shape of the
OH absorption band in the IR spectra and downfield
shift of the hydroxy proton signal in the H NMR
spectra indicate formation of a strong intramolecular
the condensation of lithium derivative II with 2,4-di-
methylbenzophenone, reported previously, the coor-
dination of lithium occurred only at the carbonyl
oxygen atom (scheme A), and the stereochemical
outcome of the reaction depended on steric and elec-
tronic properties of the carbonyl compound [6]. In
the reactions of II with 2-methoxy- and 2,4-, 2,5-, and
2,6-dimethoxybenzophenones, additional coordination
of the lithium atom at the oxygen atom of the ortho-
methoxy group in benzophenone is possible. As
a result, orientation of the carbonyl compound with
respect to the lithiated amine molecule changes, so that
the substituted benzene ring of benzophenone appears
closer to molecule II (scheme B).
1
hydrogen bond in all amino alcohols III–VIII.
Diastereoisomeric δ-amino alcohols III–V were
formed at a ratio of 1:1 (according to the intensity
1
ratio of the NMe2 and CHCH3 signals in the H NMR
spectra). This result was unexpected, for we supposed
that steric electronic effects of even one methoxy
group in the ortho position of benzophenone would be
sufficient to ensure stereoselective reaction. Therefore,
one more factor should be taken into account, namely
possible coordination of the lithium atom in II at
the oxygen atom of the ortho-methoxy group. Such
coordination could change mutual orientation of the
reacting species in the transition state. We thus pre-
sumed two possible condensation schemes A and B. In
The absence of stereoselectivity in the formation
of amino alcohols III–V indicates that both schemes,
A and B are equiprobable, i.e., the contribution of the
coordination factor is approximately equal to the joint
effect of the steric and electronic factors of two meth-
oxy groups. Analysis of molecular models showed the
lithium atom can coordinate only to an ortho-substit-
uent having a heteroatom with a lone electron pair.
This is supported by the lack of stereoselectivity in the
condensation of lithium derivative II with benzophe-
nones having a methoxy group in the ortho position
and by 100% stereoselectivity in the condensation of II
with 3,4-dimethoxybenzophenone. In the latter case,
only one diastereoisomeric amino alcohol with S-con-
figuration of the chiral center is obtained; i.e., ap-
proach of the reactants follows scheme A [7]. If
a benzophenone molecule contains only one ortho
R
OMe
R
O
O
OMe
H
H
Me
Me
Me
Me
N
N
Li
Li
Me
Me
A
B
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

DEM’YANOVICH et al.
558
substituent (o-MeO) capable of coordinating lithium
atom, its approach by the substituted ring may become
predominating, and the stereoisomer ratio should differ
from equimolar. In fact, the condensation of II with
2-methoxybenzophenone gave a mixture of diastereo-
isomeric amino alcohols VI at a ratio of 3:2.
crystals with the following unit cell parameters: a =
9.268(2), b = 8.802(2), c = 13.175(3) Å; β = 94.01(3)°,
V = 1072.1(4) Å3; dcalc = 1.21 g/cm3; z = 2; space group
P21. The structure was solved by the direct method and
was refined by the least-squares procedure in full-
matrix approximation. All hydrogen atoms were
visualized by the difference synthesis of electron dens-
ity. The position of the hydroxy hydrogen atom was
refined in isotropic approximation, and the positions
of the other hydrogen atoms were refined using the
rider model. In the calculations, 2287 reflections with
I > 2σ(I) were used. The final divergence factors were
R(F) = 0.037 and ωR(F2) = 0.097, GOF = 1.04.
We failed to separate diastereoisomeric δ-amino
alcohols III–V by chromatography, but in the reaction
with 2,5-dimethoxybenzophenone we isolated pure
amino alcohol (R,R)-IV which partially crystallized
from the mixture. The (R)-configuration of the new
chiral center (C1) was established by X-ray analysis
taking into account the known (R)-configuration of the
C8 center in the initial amine (see figure) [amino
alcohol IV was obtained from (R)-N,N-dimethyl-1-
phenylethylamine, [α]D20 = 69° (neat)].
A high stereoselectivity was observed in the con-
densation of II with 4-methoxy-2'-methylbenzophe-
none: diastereoisomeric alcohols VIII were formed at
a ratio of 6:1. Here, the situation is analogous to the
previously described reaction with 2,4'-dimethylbenzo-
phenone (diastereoisomer ratio 9:1) [6].
Amino alcohols III–VIII (general procedure).
A solution of 0.01 mol of lithium derivative II {ob-
tained from amine (S)-I, [α]2D0 = –69° (neat)} in a 1:1
hexane–diethyl ether mixture was added dropwise with
stirring under dry argon to a solution of 0.011 mol
of the corresponding substituted benzophenone in 20–
30 ml of dry diethyl ether. The mixture was stirred
for 12 h and treated with 5–10 ml of water, and the
aqueous phase was separated and extracted with di-
ethyl ether (3×20 ml). The extracts were combined
with the organic phase and washed with water and
dilute (1:1) hydrochloric acid, the acid solution was
made alkaline and extracted with diethyl ether, the
extract was dried over MgSO4, and the solvent was
distilled off. Unreacted amine I was removed by
vacuum distillation, bp 65°C (10 mm), and the residue
was crystallized from appropriate solvent. The dia-
stereoisomer ratio in the resulting amino alcohols III–
We made an attempt to estimate the contributions
of steric, electronic, and coordination factors using
2-methoxy-4,6-dimethylbenzophenone as carbonyl
substrate. As a result, a mixture of diastereoisomeric
amino alcohols VII was obtained at a ratio of 4:1. As
shown in [6], the condensation of II with 2,4,6-tri-
methylbenzophenone is completely diastereoselective,
i.e., it occurs according to scheme A. Replacement of
one ortho-methyl group by methoxy reduces the
stereoselectivity, indicating an appreciable contribution
of scheme B due to coordination of lithium at the
ortho-methoxy group. We cannot still conclude which
approach, A or B, is preferred.
1
VIII was determined from the H NMR spectra of the
reaction mixtures.
2,4-Dimethoxyphenyl[(S)-o-(1-dimethylamino-
ethyl)phenyl]phenylmethanol (III). Diastereoisomer
ratio 1:1, yield 79%, mp 131°C (from ethanol), [α]D20 =
–91.9° (c = 1, ethanol). IR spectrum: νOH 3200–
EXPERIMENTAL
1
2700 cm–1. H NMR spectrum, δ, ppm: 1.08 d and
The IR spectra were recorded in hexachloro-1,3-
1.15 d (3H, CH3CH), 2.04 s and 2.09 s [6H, N(CH3)2],
3.30 s and 3.47 s (3H, o-CH3O), 3.78 s and 3.80 s
(3H, p-CH3O), 3.89 q and 3.94 q (1H, CHCH3), 6.37–
7.42 m (12H, Harom), 9.23 s (1H, OH). Found, %:
C 76.69; H 7.63; N 3.42. C25H29NO3. Calculated %:
C 76.69; H 7.47; N 3.58.
1
butadiene on a UR-20 spectrometer. The H NMR
spectra were obtained on a Varian XR-400 spectrom-
eter (400 MHz) from solutions in CDCl3 using tetra-
methylsilane as internal reference. The optical rota-
tions ([α]D20) were measured on an EPO-1 polarimeter
(VNIEKIPRODMASh) from solutions in ethanol using
2.5- and 1-cm cells.
2,5-Dimethoxyphenyl[(R)-o-(1-dimethylamino-
ethyl)phenyl]phenylmethanol (IV) was synthesized
from (R)-N,N-dimethyl-1-phenylethylamine (R)-(I),
[α]D20 = 69° (neat). Diastereoisomer ratio 1:1. Oily sub-
stance, yield 77%, [α]D20 = 97.1° (c = 1, ethanol). IR
X-Ray diffraction study of a single crystal of amino
alcohol (S)-IV was performed on an Enraf–Nonius
CAD-4 diffractometer (MoKα irradiation, graphite
monochromator) at room temperature. Monoclinic
1
spectrum: νOH 3200–2470 cm–1. H NMR spectrum, δ,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005

STEREOCHEMICAL FEATURES OF THE CONDENSATION
559
ppm: 0.95 d and 1.10 d (3H, CH3CH), 1.95 s and
2.05 s [6H, N(CH3)2], 3.11 s and 3.20 s (3H, o-CH3O),
3.55 s and 3.62 s (3H, m-CH3O), 3.91 q (1H, CHCH3),
6.61–8.23 m (12H, Harom).
(c = 2, ethanol). IR spectrum: νOH 3300–2900 cm–1.
1H NMR spectrum, δ, ppm: 1.07 d and 1.09 d (3H,
CH3CH), 2.08 s and 2.14 s [6H, N(CH3)2], 2.21 s and
2.22 s (3H, p-CH3), 2.27 s and 2.22 s (3H, o-CH3),
3.70 s and 3.71 s (3H, o-CH3O), 3.93 q and 3.81 q (1H,
CHCH3), 6.50–8.05 m (11H, Harom), 10.11 s (1H, OH).
Found, %: C 79.98; H 8.24. C26H31NO2. Calculated,
%: C 80.17; H 8.02.
(R,R)-2,5-Dimethoxyphenyl-o-(1-dimethylamino-
ethyl)phenyl]phenylmethanol (R,R)-(IV) was isolat-
ed by recrystallization of diastereoisomer mixture IV
from hexane, mp 146°C (from ethanol), [α]D20 = 113.1°
1
(c = 1, ethanol). H NMR spectrum, δ, ppm: 1.09 d
4-Methoxyphenyl[(S)-o-(1-dimethylaminoethyl)-
phenyl]-2-tolylmethanol (VIII). Diastereoisomer
ratio 6:1, yield 59.5%, oily substance, [α]D20 = –102.5°
(c = 1, ethanol). IR spectrum: νOH 3200–2400 cm–1.
1H NMR spectrum, δ, ppm: 1.10 d and 1.15 d (3H,
CH3CH), 2.08 s and 2.23 s [6H, N(CH3)2], 2.35 s and
2.26 s (3H, o-CH3), 3.60 s and 2.99 s (3H, p-CH3O),
4.03 q and 3.90 q (1H, CHCH3), 6.40–8.02 m
(12H, Harom), 9.52 s (1H, OH). Picrate, mp 187°C
(from ethanol). Found, %: C 61.80; H 5.27; N 9.53.
C25H29NO2 · C6H3N3O7. Calculated, %: C 61.58;
H 5.34; N 9.27.
(3H, CH3CH, J = 6.78 Hz), 2.08 s [6H, N(CH3)2], 3.40 s
(3H, o-CH3O), 3.69 s (3H, m-CH3O), 3.96 q (1H,
CHCH3, J = 6.74 Hz), 6.77–7.42 m (12H, Harom),
9.40 s (1H, OH). Found, %: C 76.80; H 7.58; N 3.53.
C25H29NO3. Calculated, %: C 76.69; H 7.47; N 3.58.
2,6-Dimethoxyphenyl[(S)-o-(1-dimethylamino-
ethyl)phenyl]phenylmethanol (V). Diastereoisomer
ratio 1:1, yield 75%, [α]D20 = –18.4° (c = 1, ethanol),
mp 152°C (from ethanol). IR spectrum: νOH 3200–
1
2470 cm–1. H NMR spectrum, δ, ppm: 1.10 d and
1.32 d (3H, CH3CH), 1.94 s and 2.09 s [6H, N(CH3)2],
3.33 s and 3.35 s (3H, o-CH3O, o'-CH3O), 3.93 q and
4.12 q (1H, CHCH3), 6.40–7.52 m (12H, Harom), 8.43 s
(1H, OH). Found, %: C 76.64; H 7.69; N 3.69.
C25H29NO3. Calculated, %: C 76.69; H 7.47; N 3.58.
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[(S)-o-(1-Dimethylaminoethyl)phenyl]-2-meth-
oxyphenyl(phenyl)methanol (VI). Diastereoisomer
ratio 3:2, yield 59%, oily substance, [α]D20 = –85.1°
(c = 2, ethanol). IR spectrum: νOH 3200–2450 cm–1.
1H NMR spectrum, δ, ppm: 1.12 d and 1.17 d (3H,
CH3CH), 2.08 s and 2.13 s [6H, N(CH3)2], 3.31 s and
3.52 s (3H, o-CH3O), 3.86 q and 4.01 q (1H, CHCH3),
6.72–7.61 m (13H, Harom), 10.2 s (1H, OH). Picrate,
mp 201°C (from ethanol). Found, %: C 61.37; H 5.17;
N 9.88. C24H27NO2·C6H3N3O7. Calculated, %: C 61.01;
H 5.12; N 9.49.
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methyl-6-methoxyphenyl(phenyl)methanol (VII).
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 4 2005