A simple diastereoselective synthesis of chiral nonracemic aliphatic amines

Article abstract of DOI:10.1007/s11178-005-0248-1

An efficient procedure has been developed for the diastereoselective synthesis of chiral aliphatic amines (diastereoisomeric excess >96%) from (1S)-N-(1-methylethylidene)-1-phenylethylamine, i.e., Schiff base derived from the simplest ketone (acetone) and

Full text of DOI:10.1007/s11178-005-0248-1

Russian Journal of Organic Chemistry, Vol. 41, No. 6, 2005, pp. 807–810. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 6, 2005,
pp. 827–831.
Original Russian Text Copyright © 2005 by Grishina, Luk’yanenko, Borisenko.
A Simple Diastereoselective Synthesis of Chiral
Nonracemic Aliphatic Amines
G. V. Grishina, E. R. Luk’yanenko, and A. A. Borisenko
Faculty of Chemistry, Lomonosov Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
e-mail: grishina@org.chem.msu.su
Received July 1, 2004
Abstract—An efficient procedure has been developed for the diastereoselective synthesis of chiral aliphatic
amines (diastereoisomeric excess >96%) from (1S)-N-(1-methylethylidene)-1-phenylethylamine, i.e., Schiff
base derived from the simplest ketone (acetone) and (1S)-1-phenylethylamine. The procedure includes
successive lithiation, alkylation, and reduction and is characterized by high regioselectivity in the formation of
alkylated syn-Z-imines. Hydride reduction of the prochiral C=N bond in the latter gives mainly optically active
aliphatic amines with R configuration. All reactions are performed as a one-pot process without isolation of
intermediate products.
Enantiomerically pure amines are widely used as
chiral auxiliaries for resolution of racemic mixtures
in asymmetric synthesis, chiral ligands in metal-com-
plex catalysis, and chiral building blocks in the pre-
paration of synthetic and natural biologically active
compounds [1–5].
a one-pot process, without isolation of intermediate
products (Scheme 1). The crude products were treated
with concentrated hydrobromic acid in ethanol at
pH ~4 to obtain a mixture of the corresponding hydro-
bromides. The subsequent removal of the solvent,
drying of the residue under reduced pressure over P2O5
and fused sodium hydroxide, and recrystallization
from anhydrous ethanol–diethyl ether gave 48% of
hydrobromide Va (de 96%). According to the 1H NMR
data, the mother liquor contained an inseparable
mixture of epimeric hydrobromides at a ratio of 1.3:1
(IIIa:IVa). The ratio was determined from the intens-
ities of the methyl proton signals, δ 0.99 (IIIa) and
0.94 ppm (IVa).
In the present communication we describe an ef-
ficient stereoselective synthesis of chiral aliphatic
amines having R configuration from (1S)-N-(1-meth-
ylethylidene)-1-phenylethylamine (I) which is obtain-
ed from the simplest ketone, acetone, and (1S)-1-phe-
nylethylamine. The proposed procedure ensures more
than 96% diastereoisomeric excess. Metalation of
Schiff base I with lithium diethylamide in THF at
–20°C, followed by alkylation with methyl iodide at
–80°C and reduction with 4 equiv of sodium tetra-
hydridoborate at –80°C in the presence of 40 equiv of
isopropyl alcohol, gave a mixture of (RC,SN)- and
(SC,SN)-epimeric amines IIIa and IVa (the former
prevailing, de 79%) through intermediate syn-Z-imine
IIa. The entire reaction sequence was performed as
The structure of hydrobromides Va–Vd derived
from amines IIIa–IIId was confirmed by their anal-
1
ytical data and H and 13C NMR spectra; their pro-
perties are given in Experimental. Diastereoisomeric
1
excess was determined by H NMR spectroscopy for
the free bases in CDCl3. Optically active amines IIIb–
IIId were obtained with de 68–82%. The correspond-
Scheme 1.
Me
Me
Me
Me
Me
Me
(1) LiNEt2
(2) RHlg
NaBH4
HBr
N
Ph
N
Ph
CH2R
Z-IIa–Z-IId
HN
Ph
HN
Ph
CH2R
IVa–IVd (SC, SN)
HN
Ph
+
·HBr
Crystallization
Me
Me
Me
CH2R
Me
Me
CH2R
Va–Vd
I
IIIa–IIId (RC, SN)
RHlg = MeI (a), EtI (b), CH2=CHCH2Br (c), 4-MeC6H4CH2I (d).
1070-4280/05/4106-0807 © 2005 Pleiades Publishing, Inc.

GRISHINA et al.
808
ing diastereoisomerically pure hydrobromides Vb–Vd
(de >98%) were isolated in 31–48% yield. Below are
given the compositions of diastereoisomer mixtures
III/IV (according to the H NMR data) and chemical
shifts of the methyl protons at the new chiral center.
N-alkyl substituent in the lithiated Schiff base is more
favorable from the viewpoint of thermodynamics, and
C-alkylation of the lithium derivative is kinetically
preferred. The syn configuration of lithiated and al-
kylated imines was confirmed by ab initio calculations
[7], NMR data [8], and studies on the stereochemistry
of α-alkylation of various lithiated Schiff bases [9–11].
For example, Frazer et al. [8] performed 13C NMR
monitoring of α-alkylation of metalated Schiff bases
derived from cycloalkanones and detected only un-
stable syn-alkylated species, while Smith et al. [9]
observed formation (96%) of a very unstable syn-
alkylated Schiff base in the methylation of a metalated
butyraldehyde imine derivative.
1
Amine
IIIa/IVa IIIb/IVb IIIc/IVc IIId/IVd IIId/IVda
de, %
79
78
68
82
44
δIII, ppm
δIV, ppm
0.99
0.94
0.99
0.94
1.05
1.01
1.03
1.00
1.03
1.00
a
RHlg = 4-MeC6H4CH2Cl.
Presumably, the key stereochemical stage in the
reaction under study is formation of intermediate syn-
alkylated imines IIa–IId. The subsequent hydride
reduction of the prochiral C=N bond therein is more
favorable from the less sterically shielded re side, as
shown in Scheme 2. As a result, amines IIIa–IIId
having R configuration of the new chiral center are
mainly formed.
In order to determine the absolute configuration of
the whole series of amines IIIa–IIId we obtained op-
tically active (–)-2-butylamine (VI) by removal of the
1-phenylethyl group from amine IIIa via hydrogena-
tion over Pd/C. We then compared the signs and
magnitudes of the specific rotations of the benzoyl
derivatives of (–)-2-butylamine, [α]D20 = –30.2° (c =
4.3%, EtOH), and (+)-(2S)-2-butylamine, [α]D20 = +31°
(c = 4–5%, EtOH), whose absolute configuration is
known [12]. It is seen that their specific rotations are
almost similar in absolute values, but they have op-
posite signs. This means that (–)-2-butylamine (VI)
obtained from IIIa has R-configuration. Likewise,
comparison of the specific rotations of (2R)-2-butyl-
amine hydrochloride ([α]D20 = +4°, c = 2.96%, EtOH
Scheme 2.
Ph
Me
N
H
[H]–
[H]–
Me
CH2R
Z-IIa–Z-IId
si Approach
re Approach
The stereochemical composition of Schiff base IIa
during alkylation was monitored by 13C NMR spec-
troscopy at room temperature (the spectra of samples
withdrawn from the reaction mixture were recorded
as quickly as possible). We found that the Z and E
isomers of IIa were formed at a ratio of 3:1 (NCH:
δC 57.9 and 57.5 ppm, respectively). We believe that
an appreciable amount of E-IIa is formed via Z–E
isomerization at room temperature. This assumption is
confirmed by the fact that the reduction under the same
conditions (–80°C, 4 equiv of NaBH4, 40 equiv of iso-
propyl alcohol) of Schiff base IIa with a Z/E isomer
ratio of 1:4 (which was obtained by heating IIa for 1 h
in boiling THF) afforded diastereoisomer IVa as the
major product but with a diastereoisomeric excess
of only 43%.
[13]) and hydrochloride obtained from VI ([α]D20
=
+4.1°, c = 4.1%, EtOH) indicated identical configura-
tions of the chiral center in these compounds. There-
fore, all amines IIIa–IIId belong to the same R-series
with respect to the configuration of the new chiral
center. It should be noted that the signal from the CH3
1
group at that center in the H NMR spectra of amines
IIIa–IIId is located appreciably downfield relative to
the corresponding signals in the spectra of epimeric
amines IVa–IVd.
The diastereoselectivity in the formation of (RC,SN)-
amines IIIa–IIId depends on the nature and amount of
the alcohol added at the reduction stage. Below are
given the ratios of diastereoisomeric amines IIIa and
IVa formed by reduction of IIa with sodium tetra-
hydridoborate in the presence of different amounts of
different alcohols (according to the 1H NMR spectra of
the reaction mixtures).
The above synthetic strategy for the preparation
of optically pure (R)-amines IIIa–IIId was selected
taking into account highly regioselective formation of
syn-imines IIa–IId due to determining role of the
syn effect in the deprotonation of Schiff bases and
α-alkylation of their lithium derivatives [6]. Obviously,
the syn orientation of the carbanionic center and the
Alcohol
i-PrOH t-BuOH EtOH EtOH EtOH MeOH
Amount,
equiv
40
20
40
04
02
60
IIIa:IVa
8.5:1
7:1
6:1
3:1
1:1 1:1.25
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

A SIMPLE DIASTEREOSELECTIVE SYNTHESIS
809
These data show that the reduction of IIa in the
presence of tert-butyl alcohol (which is sparingly
soluble in the reaction mixture at low temperature) and
ethanol gives lower diastereoisomeric excess of amine
IIIa than in the presence of isopropyl alcohol (75 and
71%, respectively). In addition, decrease in the amount
of ethanol to 2 equiv leads to complete loss of dia-
stereoselectivity. This pattern may be rationalized on
the assumption that the hydride reduction is accom-
panied by Z–E isomerization. Due to high rate of Z–E
isomerization, amine IIIa is formed as minor product
in the reduction of Schiff base IIa in methanol .
for 30 min at –80°C, the cooling bath was removed,
and the mixture was allowed to warm up to room
temperature over a period of 1 h under vigorous
stirring. The solvent was removed, and the residue was
decomposed by carefully adding 6 N hydrochloric acid
until hydrogen no longer evolved. The mixture was
diluted with 20 ml of water, a 20% solution of sodium
hydroxide was added to pH 12, and the mixture was
extracted with diethyl ether (2×30 ml). The extracts
were combined, dried over anhydrous sodium sulfate,
and evaporated. The oily residue was dissolved in
10 ml of ethanol, the solution was cooled to 0°C, and
concentrated hydrobromic acid was added to a weakly
acidic reaction. The mixture was evaporated, and the
residue was dried under reduced pressure over P2O5
and fused alkali over a period of 10 h and recrys-
tallized 5 times from anhydrous ethanol–diethyl ether.
Yield 1.54 g (48%), mp 200–201°C, [α]D20 = –24° (c =
Thus we have proposed a simple and efficient
procedure for the synthesis of optically pure aliphatic
amines of the R-series from acetone and (1S)-1-phe-
nylethylamine. Naturally, (1R)-1-phenylethylamine
should give rise to the corresponding (S)-amines. The
target products are readily isolated as the correspond-
ing hydrobromides, and the procedure can be used in
enlarged syntheses. The proposed procedure comple-
ments the existing methods for reductive amination of
ketones with the use of 1-phenylethylamine [13–16].
1
3.2%, EtOH), de 96% (1H NMR data). H NMR spec-
trum (CDCl3, 400 MHz) of free base IIIa, δ, ppm:
0.82 t (3H, J = 7.5 Hz), 0.99 d (3H, J = 6.1 Hz), 1.23–
1.41 m (2H), 1.33 d (3H, J = 6.8 Hz), 2.33 sext (1H,
J = 6.1 Hz), 3.90 q (1H, J = 6.8 Hz), 7.19–7.33 m
(5H). 13C NMR spectrum (CDCl3, 100 MHz) of free
base IIIa, δC, ppm: 10.4, 19.5, 25.1, 30.6, 51.1, 54.8,
126.4, 126.6, 128.3, 146.1. Found, %: C 55.78; H 8.05;
N 5.28. C12H19N·HBr. Calculated, %: C 55.82; H 7.81;
N 5.42.
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
1
13
trometer. The H and C NMR spectra were obtained
1
on Varian XL-400 (400 MHz for H and 100 MHz
for 13C) and Bruker WM-300 spectrometers (300 MHz
[(1R)-1-Methylbutyl][(1S)-1-phenylethyl]amine
hydrobromide (Vb) was synthesized in a similar way
from 2 g (12.4 mmol) of compound I and 2.91 g
(18.6 mmol) of ethyl iodide. The product was recrys-
tallized 4 times from anhydrous ethanol–diethyl ether.
Yield 1.42 g (42%), mp 187–188°C, [α]D20 = –14° (c =
1
for H and 75 MHz for 13C). Thin-layer chromatog-
raphy was performed on Silufol plates (Kavalier,
Czechia). Tetrahydrofuran was distilled over sodium
diphenylketyl. (1S)-N-(1-Methylethylidene)-1-phenyl-
ethylamine (I) was prepared in 84% yield from acetone
and (1S)-1-phenylethylamine ([α]D20 = –40.0°, pure
grade) according to the procedure described in [17].
1
3.5%, EtOH), de 98% (1H NMR). H NMR spectrum
(CDCl3, 400 MHz) of free base IIIb, δ, ppm: 0.81 t
(3H, J = 7.0 Hz), 0.99 d (3H, J = 6.5 Hz), 1.19–1.34 m
(4H), 1.33 d (3H, J = 6.8 Hz), 2.40 m (1H), 3.90 q
[(1R)-1-Methylpropyl][(1S)-1-phenylethyl]amine
hydrobromide (Va). Metalation and alkylation of
Schiff base I were performed under argon; reactants
were added using a syringe through a septum. Com-
pound I, 2 g (12.4 mmol), was added to a solution
of lithium diethylamide, prepared from 1.36 g
(18.6 mmol) of diethylamine in 30 ml of anhydrous
THF and 11.6 ml (18.6 mmol) of a 1.6 N solution of
butyllithium in hexane by stirring for 10 min at –10°C.
The mixture was stirred for 30 min and cooled to
–80°C, 2.65 g (18.6 mmol) of methyl iodide was
added, the mixture was stirred for 30 min at –80°C,
and a suspension of 1.9 g (50 mmol) of sodium
tetrahydridoborate in 40 ml of isopropyl alcohol,
cooled to –80°C, was added. The mixture was stirred
13
(1H, J = 6.8 Hz), 7.19–7.33 m (5H). C NMR spec-
trum (CDCl3, 100 MHz) of free base IIIb, δC, ppm:
14.1, 19.1, 20.0, 25.1, 40.4, 49.3, 54.8, 126.4, 126.6,
128.3, 146.1. Found, %: C 57.32; H 8.38; N 5.07.
C13H21N·HBr. Calculated, %: C 57.36; H 8.15; N 5.15.
[(1R)-1-Methyl-4-pentenyl][(1S)-1-phenylethyl]-
amine hydrobromide (Vc) was synthesized in a si-
milar way from 2 g (12.4 mmol) of compound I and
2.25 g (18.6 mmol) of allyl bromide (after addition
of allyl bromide, the mixture was stirred for 1 h).
The product was recrystallized twice from anhydrous
acetone–diethyl ether. Yield 1.10 g (31%), mp 172–
175°C, [α]2D0 = –24° (c = 3.6%, EtOH), de >98%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005

GRISHINA et al.
810
1
(1H NMR). H NMR spectrum (CDCl3, 300 MHz) of
free base IIIc, δ, ppm: 1.01 d (3H, J = 6.3 Hz), 1.28–
1.48 m (2H), 1.33 d (3H, J = 6.7 Hz), 1.94–2.16 m
(2H), 2.42 sext (1H, J = 6.3 Hz), 3.90 q (1H, J =
6.7 Hz), 4.85–4.97 m (2H), 5.66–5.79 m (1H), 7.19–
7.34 m (5H). 13C NMR spectrum (CDCl3, 100 MHz) of
free base IIIc, δC, ppm: 20.0, 25.1, 30.4, 37.3, 49.3,
54.8, 114.2, 138.8, 126.5, 126.7, 128.3, 138.8, 146.0.
Found, %: C 59.20; H 8.04; N 4.86. C14H21N·HBr.
Calculated, %: C 59.16; H 7.80; N 4.93.
C 43.87; H 11.33; N 12.65. C4H11N·HCl. Calculated,
%: C 43.84; H 11.04; N 12.78. Benzoyl derivative:
mp 95–96°C, [α]D20 = –30.2° (c = 4.3%, EtOH).
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was filtered off, the filtrate was evaporated, and the
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1
(c = 4.1%, EtOH), de 97%. H NMR spectrum
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 6 2005