Synthesis and characterization of chiral 1,2-diamines from 5-oxo-pyrrolidine-(S)-2-carboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2007.07.012

Unsymmetrical chiral secondary vicinal diamines were synthesized by applying a modified three-step reaction. The key step in this sequence is a primary amine mediated ring opening reaction of a diastereomeric oxazolidinone derivative. A possible mechanism

Full text of DOI:10.1016/j.tetasy.2007.07.012

Tetrahedron: Asymmetry 18 (2007) 1735–1741
Synthesis and characterization of chiral 1,2-diamines
from 5-oxo-pyrrolidine-(S)-2-carboxylic acid
Uwe Kohn,a Andrea Schramm,a Florian Kloß,a Helmar Gorls,b
¨
¨
Evelyn Arnolda and Ernst Andersa,*
aInstitut fu¨r Organische und Makromolekulare Chemie der Friedrich-Schiller-Universita¨t, Humboldtstr. 10, D-07745 Jena, Germany
bInstitut fu¨r Anorganische und Analytische Chemie der Friedrich-Schiller-Universita¨t, Lessingstr. 8, D-07743 Jena, Germany
Received 2 July 2007; accepted 16 July 2007
Abstract—Unsymmetrical chiral secondary vicinal diamines were synthesized by applying a modified three-step reaction. The key step in
this sequence is a primary amine mediated ring opening reaction of a diastereomeric oxazolidinone derivative. A possible mechanism for
this step is described.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ferent protected C2 symmetric 1, n-diamines in high diaste-
reo- and enantiomeric purity.7 An efficient aldimine cross-
coupling route to unsymmetrical vicinal diamine com-
pounds capitalizes upon the reaction of N-monosubstituted
a-amino nitriles and imines as exploited by Opatz et al. in
2005.8 Recent work by Wang et al. using chiral b-amino
imines selectively afforded after reduction with different
reducing agents syn- or anti-1,3-diamines in high diastereo-
selectivities.9 Denmark et al. reported the synthesis of
several enantiopure 1,2-diphenyl-1,2-ethanediamine com-
pounds by the reductive coupling of the corresponding
N-silylimine derivates with NbCl4(THF)2.10 A general
route to chiral vicinal diamines via the formation of a 2-tri-
chloromethyloxazolidin-4-one precursor, a ring opening
reaction with secondary amines and subsequent reduction
has been described by Amedjouk et al.11 The strategy of
oxazolidinone formation during the first step is derived
from the self-reproduction of chirality methodology of
Seebach et al.,12 which was modified by Wang and
Germanas.13
Various compounds with a biologically active vicinal di-
amine function play an important role in medicinal chem-
istry as anti-depressant agents, anti psychotics, cytostatics
or antihypertensives.1 Moreover, vicinal 1,2-diamine deriv-
atives are important compounds or key structural units in
organic and supramolecular chemistry as valuable interme-
diates,2 additives for metal organic compounds, and as syn-
thetic components for the building of nitrogenous
macrocycles (cryptates).3 Enantiopure 1,2-diamines are
used as chiral auxiliaries or ligands and have achieved con-
siderable importance in stereoselective syntheses.4 Lucet,
Le Gall and Mioskowski reviewed the chemistry of vicinal
diamines in 1998.1 Since that report, the development of
new or improved synthetic methods of diamines and their
applications has continued. Alexakis et al. reported the
synthesis of a new tertiary pseudo C2-symmetric 1,2-di-
amine derived from (1S,2S)-(+)-pseudoephedrine, which
was subsequently applied as a chiral auxiliary in the enan-
tioselective addition of MeLi to aromatic imines.5 Re-
cently, Alexakis et al. described the further synthesis of a
chiral 1,2-diamine with C2 symmetry and its successful
application as an auxiliary.6 Enders et al. have developed
an efficient and flexible method for the preparation of dif-
In continuation of our interest in chiral guanidine chemis-
try14 we have focused our attention onto the synthesis of
chiral 1,2-diamine compounds with two NH functions.
With Amedjouk‘s three-step procedure in hand, we devel-
oped an alternative and efficient approach, which involves
the ring opening reaction between diastereomeric oxazolid-
inone intermediates and different primary aliphatic and
aromatic amines as the key step. Herein, we report the
*
Corresponding author. Tel.: +49 0 3641 948210; fax: +49 0 3641
948212; e-mail: Ernst.Anders@uni-jena.de
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.07.012

1736
U. Ko¨hn et al. / Tetrahedron: Asymmetry 18 (2007) 1735–1741
synthesis of unsymmetrical chiral vicinal diamines via a
three-step reaction starting with commercially available 5-
oxo-pyrrolidine-2-carboxylic acid as the chiral source.
2. Results and discussion
The starting point of the three-step reaction is the synthesis
of the known diastereomeric oxazolidinone derivative 1,
which was performed by the reaction of equivalent
amounts of 5-oxo-pyrrolidine-(S)-2-carboxylic acid and
anhydrous chloral in the presence of catalytic amounts of
p-toluenesulfonic acid in toluene (Scheme 1, a).11
O
a
O
O
O
N
OH
N
H
O
Cl3C
1
b
Figure 1. Molecular structure of 1.
O
asymmetric carbon atom does not change its configuration
during the reaction sequence. The absolute configuration
of the newly formed asymmetric centre C(6) was deter-
mined to be (R)-configuration.
c
O
NR
H
N
NR
H
N
H
H
3a-i
2a-i
Treatment of 1 (1 equiv) with primary aromatic amines
(3 equiv) in refluxing toluene (30 mL) for 2 h afforded, via
a nucleophilic oxazolidinone ring opening reaction, N-
aryl-5-oxopyrrolidine-(S)-2-carboxamides 2a–i in high
yields (Scheme 1, b, Table 1). Under these optimized con-
ditions, amide compounds 2a–i partly separated as solid
during the reflux procedure and could be obtained upon fil-
tration in high purity. Filtration of the slightly warm reac-
tion mixture was found to be an appropriate procedure for
obtaining 2a–i in high enantiomeric excess.
Scheme 1. The synthesis of chiral vicinal diamines 3a–i. Reagents and
conditions: (a) 5-oxo-L-proline, anhydrous chloral, toluene, reflux, 40 h;
(b) 1, primary amines (cf. Table 1) , toluene, reflux, 2 h; (c) 2a–i, LiAlH4,
THF, reflux, 2 h.
Upon refluxing for 40 h and filtration of the hot reaction
mixture, the air-stable diasteromeric compound 1 was
obtained in yields over 90%. Our NMR investigations
confirmed the formation of only one diastereomeric form
1
of 1 according to the literature.11 The H NMR spectrum
of compound 1 exhibited a sharp singlet at d = 6.05 ppm
for the formation of the characteristic hemiaminal func-
tion. The corresponding 13C NMR signal was detected at
d = 92.2 ppm. In addition, the structure of the oxazolidi-
none derivate 1 and, accordingly the, configurations of
the two stereogenic centres [C(2), C(6)] were firmly estab-
lished by using X-ray crystallographic analysis. Suitable
single-crystals were obtained by crystallisation from ethyl
acetate. As shown in Figure 1, the predetermined (S)-con-
figuration at the C(2) carbon could be confirmed, since the
However, this filtration procedure is accompanied by a
minor decrease of the yields. For compound 2c, the
increase in the steric hindrance of the nucleophilic nitrogen
atom caused by the methyl groups at the o/o0-positions led
to an extension of the reaction time (6 h). All products 2a–i
were fully characterized by NMR spectroscopy, mass
spectrometry and elemental analysis. The 1H NMR spectra
of 2a–i in deuterated DMSO revealed the presence of
two amide NH signals in the characteristic range of
Table 1. Preparation of N-aryl-5-oxopyrrolidine-(S)-2-carboxamides 2a–i and the corresponding vicinial diamines 3a–i
rt
Primary amine
Chiral diamides
Yieldsa (%)
Chiral 1,2-diamines
Yieldsa (%)
½aꢀD
Aniline
p-Toluidine
2a
2b
2c
2d
2e
2f
95.4
98.0
77.4
84.0
73.6
97.0
99.1
81.7
98.4
3a
3b
3c
3d
3e
3f
44.7
80.2
38.1
70.7
64.1
47.0
34.1
53.6
49.2
31.0
29.5
23.25
27.1
2,4,6-Trimethylaniline
4-Chloroaniline
a-Naphthylamine
Benzylamine
p-Methylbenzylamine
(R)-Phenylethylamine
(S)-Phenylethylamine
52.0
15.15
14.95
27.1
ꢁ15.3
2g
2i
3g
3i
2h
3h
a Isolated yields.

U. Ko¨hn et al. / Tetrahedron: Asymmetry 18 (2007) 1735–1741
1737
7–11 ppm, which indicate that the nucleophilic ring open-
ing reaction, by means of primary aromatic amines, has
occurred. The final evidence for the existence of the two
NH protons was found by HMQC and HMBC NMR
correlation experiments. Using the reaction conditions
described in the literature,11 we observed in all our at-
tempts no or only minor ring opening reaction products.
In addition, we performed NMR investigations of the
resulting filtration solution of 2b to obtain insight into
the oxazolidinone ring opening reaction. The residue
obtained upon the removal of the solvent and stirring in
petrol ether was determined to be the N-tolylaminal of
>96%) were obtained. It should be noted that the washing
step of the residue with hot THF during the aqueous work-
up is very important for obtaining yields of the crude prod-
ucts over 90%. The enantiomeric excesses of diamines 3a–i
were determined by using a chiral stationary phase (Daicel
Chiracel OD–H column).18 The ability to separate the
enantiomers with the HPLC method used was shown by
comparison with the racemic compounds of diamines 3a–
i. The preservation of the given (S)-configuration of the
starting material is shown by the polarimetric data of 3a–
i and their comparison with known diamines. Additionally,
the structural analysis of 3d to confirm the absolute config-
uration of vicinal diamines 3a–i has been performed using
X-ray crystallography. It should be noted that the vicinal
diamines 3b and 3d crystallize at room temperature after
standing for several days.
1
chloral 415 by NMR analysis, including H, 13C, HMQC
and HMBC experiments and elemental analysis. Aminal
4 was characterized by two peaks at d = 75.7 (CH) and
d = 104.6 (Cl3C) ppm in the 13C NMR spectrum. In the
1H NMR spectrum, the observed peaks at d = 5.83 ppm
and d = 5.57 ppm were assigned to both the NH and CH
protons, respectively. Their characteristic CH3 group reso-
nances were observed as a singlet at d = 2.13 ppm.
The X-ray structural data of the isolated crystals of 3d con-
firmed the preservation of the (S)-configuration at the C2
carbon in 5-oxo-pyrrolidine-(S)-2-carboxylic acid during
the three-step reaction (Fig. 2). All chiral 1,2-diamines
3a–i were fully characterized by 1D and 2D NMR
(HMCQ, HMBC, and COSY) measurements and high res-
olution mass-spectrometry investigations. Their 13C NMR
spectra generally exhibit the expected number of signals
and show the loss of the two amide C@O signals indicating
the successful reduction of 2a–i.
In order to explain the formation of 4, we performed the
reaction of 1 with 2 equiv of p-toluidine and investigated
1
the resulting filtration solution by NMR analysis. The H
and 13C NMR studies showed that the tolylimine of chloral
5,16 2,2,2-trichloroethylidene-p-toluidine, was formed dur-
ing this step.
A plausible mechanism for the ring opening is shown in
Scheme 2. According to NMR data obtained, we can
assume that the lactone functionality of 1 was converted
under ring opening to the corresponding amide group
and a hemiaminal unit by the nucleophilic attack of the
first equivalent p-toluidine. Under our chosen reflux
conditions an excess of p-toluidine led directly to the
formation of vicinal diamide 2b and a carbinolamine based
on chloral. This carbinolamine likely undergoes a dehydra-
tion to form imine 5 followed by the addition of p-toluidine
to the imine function generating aminal 4.17
Figure 2. Molecular structure of 3d.
Finally, the resulting diamides 2a–i were converted without
further purification into the corresponding chiral 1,2-diam-
ines 3a–i by reduction with lithium aluminium hydride.
Diamides 2a–i were added to a THF suspension of LiAlH4
and heated at refluxing for 2 h at this juncture. Upon aque-
ous basic workup, the purification of 3a–i was carried out
by bulb to bulb distillation, in which moderate to good
yields (34–80%) and very high enantioselectivities (ee
3. Conclusion
In conclusion, an improved and efficient three-step meth-
odology has been successfully applied to synthesize unsym-
metrical enantiopure 1,2-diamines with two secondary
amine functions. This vicinal diamine method demon-
O
NHR
p-toluidine
p-toluidine
NHR
O
1
2b
N
+
Cl3C
OH
R: p-tolyl
Cl3C
OH
H
C
NHR
NHR
Cl3C
p-toluidine
NR + H2O
Cl3C
H
5
4
Scheme 2. Proposed mechanism for step 2.

1738
U. Ko¨hn et al. / Tetrahedron: Asymmetry 18 (2007) 1735–1741
strates good generality, since the synthesized chiral 1,2-
diamines can be derived from commercially available 5-
oxo-L-proline and a variety of primary aromatic amines.
The easy accessibility and the stability over a long period
of time of these chiral 1,2-diamines make them useful as
possible chiral ligands for catalysts in asymmetric
syntheses.
DMSO-d6, rt): d = 10.00 (s, NH), 7.89 (s, NH), 7.61 (d,
3
3J = 8.8 Hz, 2 · CH), 7.30 (t, J = 7.7 Hz, 2 · CH), 7.05
(t, 3J = 7.3 Hz, CH), 4.19 (m, CH), 2.31/1.99 (m, COCH2),
2.17 (m, CH2) ppm. 13C NMR (62.9 MHz, DMSO-d6, rt):
d = 177.4 (CO), 171.2 (CO), 138.7 (C), 128.7 (2 · CH),
123.4 (CH), 119.3 (2 · CH), 56.3 (CH), 29.2 (COCH2),
25.3 (CH2) ppm. MS (EI, 70 eV): m/z (%) = 204 (60)
[M+], 84 (100) [MꢁC7H6NO]+.
4. Experimental
4.1. General
4.2.3. N-Tolyl-5-oxo-pyrrolidine-(S)-2-carboxamide 2b.20
20
Yield 98.0%, mp 206–208 ꢁC (fawn solid). ½aꢀD
¼
þ16:11 (c 2.11, DMSO). Found: C, 65.79; H, 6.41;
N 12.72. C12H14N2O2 requires C, 66.04; H, 6.47; N,
12.86. IR (ATR): 3319, 3247, 3124, 3083, 3053, 1687,
NMR spectra were recorded on a Bruker AC 250 MHz and
AC 400 MHz using the residual solvent resonance as an
internal standard. CDCl3 (H d = 7.24, C d = 77.0 ppm)
and DMSO-d6 (H d = 2.49, C d = 35.5 ppm) were used as
solvent. The geminal protons of the CH2 groups were listed
as d = X/X ppm. The multiplicities of the 13C NMR signals
were determined with the DEPT 135 technique. Optical
1
1660, 1612, 1509 cmꢁ1. H NMR (250 MHz, DMSO-d6,
3
rt): d = 9.32 (s, NH), 7.68 (s, NH), 7.49 (d, J = 8.4 Hz,
2 · CH), 7.01 (d, 3J = 8.4 Hz, 2 · CH), 4.16 (m, CH),
2.28/2.15 (m, COCH2), 2.23 (s, CH3), 2.18 (m, CH2)
ppm. 13C NMR (62.9 MHz, DMSO-d6, rt): d = 177.4
(CO), 171.0 (CO), 136.2 (C), 132.4 (C), 129.3 (2 · CH),
119.3 (2 · CH), 56.3 (CH), 29.2 (COCH2), 25.2 (CH2),
20.4 (CH3) ppm. MS (EI, 70 eV): m/z (%) = 218 (50)
[M+], 84 (100) [MꢁC4H6NO]+.
rotations were recorded on a Polartronic E and are re-
rt
ported as ½aꢀD (c in g per 100 mL, solvent). Elemental anal-
yses were conducted by the microanalytical service of our
department. IR spectra were recorded on an ATR–BIO-
RAD FTS-25. MS spectra were recorded on a Finnigan
MAT SAQ 710 (EI). All compounds were fully character-
ized and given microanalytical data ( 0.4%) or HRMS
(Micro-ESI). Enantiomeric purity was determined on a
Jasco liquid chromatograph with a Knauer UV detector,
using a Daicel Chiralcel ODH column. 5-Oxo-pyrroli-
dine-(S)-2-carboxylic acid, anhydrous chloral and the cor-
responding amine were commercially available and used
without further purification.
4.2.4. N-Mesityl-5-oxo-pyrrolidine-(S)-2-carboxamide 2c.
20
Yield 77.4%, mp 255 ꢁC (white solid). ½aꢀD ¼ þ23:4 (c
2.22, DMSO). Found: C, 68.12; H, 7.45; N, 11.35.
C14H18N2O2 requires C, 68.27; H, 7.37; N 11.37. IR
(ATR): 3233, 3081, 2914, 2856, 1709, 1659, 1610, 1525,
1
1484 cmꢁ1. H NMR (250 MHz, DMSO-d6, rt): d = 9.25
(s, NH), 7.94 (s, NH), 6.86 (s, 2 · CH), 4.21 (m, CH),
2.49 (m, COCH2), 2.21 (s, CH3), 2.18/2.05 (m, CH2), 2.08
(s, 2 · CH3) ppm. 13C NMR (62.9 MHz, DMSO-d6, rt):
d = 177.3 (CO), 171.0 (CO), 135.4 (C), 134.8 (2 · C),
131.9 (C), 128.6 (2 · CH), 55.8 (CH), 29.3 (COCH2), 25.6
(CH2), 20.4 (CH3), 17.8 (2 · CH3) ppm. MS (EI, 70 eV):
m/z (%) = 246 (60) [M+], 135 (100) [MꢁC5H5NO2]+.
4.2. General procedure for the preparation of chiral carb-
oxamides 2a–i
4.2.1. (2R,5S)-2-Trichloromethyl-1-aza-3-oxabicyclo-[3,3,0]-
octan-4,8-dione 1. Compound 1 was synthesized accord-
ing to the published procedure of Amedjkouh and Ahl-
berg,11 in which we have increased the reaction time from
16 to 40 h.
4.2.5. N-(4-Chlorophenyl)-5-oxo-pyrrolidine-(S)-2-carbox-
amide 2d.21 Yield 84.0%, mp 202–204 ꢁC (fawn solid).
20
½aꢀD ¼ þ13:8 (c 2.18, DMSO). Found: C, 55.29; H, 4.61;
N, 11.64. C11H11N2O2Cl requires C, 55.36; H, 4.65; N,
11.74. IR (ATR): 3328, 3242, 3228, 3119, 3078, 1690,
1
Diastereomer 1 (2 g, 7.75 mmol) and the corresponding
primary aliphatic or aromatic amine (23.3 mmol) were dis-
solved in toluene (30 mL) followed by reflux for 2 h. For
2c, the amount of toluene (60 mL) and the reaction time
(6 h) were increased. It should be noted that in the majority
of cases the products were separated from the solution dur-
ing the refluxing. After refluxing, the reaction mixture was
allowed to cool gradually to 50 ꢁC and was then filtered.
The solid obtained was washed with diethyl ether and
was dried in vacuum. The purity could be further increased
by re-crystallization from ethyl acetate/ethanol or ethyl
acetate.
1663, 1613, 1595, 1550, 1489 cmꢁ1. H NMR (250 MHz,
DMSO-d6, rt): d = 10.20 (s, NH), 7.87 (s, NH), 7.64 (d,
3
3J = 8.8 Hz, 2 · CH), 7.36 (d, J = 8.4 Hz, 2 · CH), 4.17
(m, CH), 2.31/2.03 (m, COCH2), 2.16 (m, CH2) ppm. 13C
NMR (62.9 MHz, DMSO-d6, rt): d = 177.4 (CO), 171.4
(CO), 137.7 (C), 128.6 (2 · CH), 127.0 (C), 120.9
(2 · CH), 56.4 (CH), 29.1 (COCH2), 25.2 (CH2) ppm. MS
(EI, 70 eV): m/z (%) = 238 (30) [M+], 84 (100)
[MꢁC7H5ClNO]+.
4.2.6. N-(1-Naphthyl)-5-oxo-pyrrolidine-(S)-2-carboxamide
2e.22 Yield 73.6%, mp 210 ꢁC (paly violet solid).
20
½aꢀD ¼ þ34:65 (c 2.02, DMSO). Found: C, 70.50; H, 5.53;
4.2.2. N-Phenyl-5-oxo-pyrrolidine-(S)-2-carboxamide 2a.19
N, 10.99. C15H14N2O2 requires C, 70.85; H, 5.55; N,
11.02. IR (ATR): 3246, 3053, 1717, 1667, 1541,
20
Yield 95.4%, mp 185 ꢁC (white solid). ½aꢀD ¼ þ14:1
1
(c 2.27, DMSO). Found: C, 64.69; H, 5.92; N, 13.67.
C11H12N2 O2 requires C, 64.69; H, 5.92; N, 13.72. IR
(ATR): 3322, 3255, 3198, 3140, 3092, 1685, 1661, 1619,
1504 cmꢁ1. H NMR (250 MHz, DMSO-d6, rt): d = 10.03
(s, NH), 8.10–7.45 (m, 7 · CH), 8.00 (s, NH), 4.42 (m,
CH), 2.41/2.12 (m, COCH2), 2.21 (m, CH2) ppm. 13C
NMR (62.9 MHz, DMSO-d6, rt): d = 177.4 (CO), 172.0
1601, 1552, 1483, 1445 cmꢁ1
.
1H NMR (250 MHz,

U. Ko¨hn et al. / Tetrahedron: Asymmetry 18 (2007) 1735–1741
1739
(CO), 136.6 (C), 136.0 (C), 127.9 (C), 128.1, 126.4, 125.8,
4.3. General procedure for the preparation of chiral
1,2-diamines
2 · 125.5, 122.7, 121.9 (7 · CH), 56.1 (CH), 29.3 (COCH2),
25.5 (CH2) ppm. MS (EI, 70 eV): m/z (%) = 254 (60) [M+],
143 (100) [MꢁC5H5NO2]+.
Anhydrous THF (50 mL) was added to LiAlH4
(23.3 mmol) under an argon atmosphere and the mixture
was cooled to 0 ꢁC. Upon slow addition of the solid carb-
oxamides 2a–i (2 g, 7.75 mmol), the resulting mixture was
refluxed for 2 h until the reduction was completed as mon-
itoring by IR and 13C NMR spectroscopies. The reaction
mixture was then treated with aqueous 2 M NaOH solu-
tion under ice bath cooling until the reaction was com-
pleted by forming a solid residue. After stirring for 2 h at
room temperature, the mixture was filtered and the solid
residue washed with hot THF (50 mL). The combined
organic phases were dried over MgSO4 and concentrated
in vacuum to afford a crude yellow oil. Purification of the
residue by bulb-to-bulb distillation gave 3a–i as colourless
to light yellow oils.
4.2.7. N-Benzyl-5-oxo-pyrrolidine-(S)-2-carboxamide 2f.11
20
Yield 97.0%, mp 130 ꢁC (white solid). ½aꢀD ¼ þ13:7 (c
2.04, DMSO). Found: C, 66.00; H, 6.53; N, 12.73.
C12H14N2O2 requires C, 66.04; H, 6.46; N, 12.83. IR
(ATR): 3273, 3226, 1682, 1639, 1572 cmꢁ1 1H NMR
.
(250 MHz, DMSO-d6, rt): d = 8.48 (s, NH), 7.84 (s, NH),
7.37–7.18 (m, 5 · CH), 4.28 (d, 3J = 5.74 Hz, Ph–CH2),
4.03 (m, CH), 2.27/1.89 (m, COCH2), 2.12 (m, CH2)
ppm. 13C NMR (62.9 MHz, DMSO-d6, rt): d = 177.3
(CO), 172.3 (CO), 139.1 (C), 128.2, 127.1, 126.7 (5 · CH),
55.8 (CH), 42.0 (CH2), 29.1 (COCH2), 25.3 (CH2) ppm.
MS (EI, 70 eV): m/z (%) = 218 (10) [M+], 84 (100)
[MꢁC8H8NO]+.
4.2.8. N-(4-Methylbenzyl)-5-oxo-pyrrolidine-(S)-2-carbox-
amide 2g.23 Yield 99.1%, mp 128 ꢁC (white solid).
4.3.1.
N-(Pyrrolidin-2-ylmethyl)-aniline
3a.10 Yield
20
44.7%, bp 147 ꢁC/5.0 · 10ꢁ2 Torr (colourless oil). ½aꢀD
¼
20
½aꢀD ¼ þ7:8 (c 2.04, DMSO). Found: C, 67.22; H, 6.94;
þ31:0 (c 4.77, CHCl3). HRMS m/z 177.1369 [M+H]+.
N 12.06. C13H16N2O2 requires C, 67.22; H, 6.94; N,
12.06. IR (ATR): 3288, 3082, 2918, 1697, 1655, 1647,
C11H17N2 requires 177.1392. IR (ATR): 3326, 2956, 2868,
1601, 1502, 746 cmꢁ1 1H NMR (250 MHz, CDCl3, rt):
.
1533, 1516 cmꢁ1
.
1H NMR (250 MHz, DMSO-d6, rt):
d = 7.04 (m, CH), 6.55 (m, 2 · CH), 6.50 (m, 2 · CH),
5.38 (s, NH), 3.19 (m, CH), 2.91 (m, CH2), 2.77 (m,
CH2), 2.62 (s, NH), 1.77/1.35 (m, CH2), 1.64 (m, CH2)
ppm. 13C NMR (62.9 MHz, CDCl3, rt): d = 149.1 (C),
128.7 (2 · CH), 115.4 (CH), 111.9 (2 · CH), 56.9 (CH),
48.1 (CH2), 45.7 (CH2), 29.2 (CH2), 25.1 (CH2) ppm.
d = 8.45 (s, NH), 7.84 (s, NH), 7.12 (m, 4 · CH), 4.21 (d,
3J = 5.7 Hz, Ph–CH2), 4.02 (m, CH), 2.26 (s, CH3), 2.22/
1.87 (m, 2H, COCH2), 2.12 (m, CH2) ppm. 13C NMR
(62.9 MHz, DMSO-d6, rt): d = 177.3 (CO), 172.2 (CO),
136.1 (C), 135.8 (C), 128.7 (2 · CH), 127.2 (2 · CH), 55.8
(CH), 41.8 (CH2), 29.2 (COCH2), 25.3 (CH2), 20.6 (CH3)
ppm. MS (EI, 70 eV): m/z (%) = 232 (10) [M+], 84 (100)
[MꢁC9H10NO]+.
4.3.2. 4-Methyl-N-(pyrrolidin-2-ylmethyl)-aniline 3b.24
Yield 80.2%, bp 125 ꢁC/1.0 · 10ꢁ2 Torr (colourless oil),
3b crystallize after standing for several days at room tem-
4.2.9. N-(R)-1-Phenylethyl-5-oxo-pyrrolidine-(S)-2-carbox-
amide 2h.11 Yield 98.4%, mp 151 ꢁC (white solid).
perature, mp 112 ꢁC. HRMS m/z 191.1542 [M+H]+
20
C12H19N2 requires 191.1543. ½aꢀD ¼ þ29:5 (c 2.85, CHCl3).
20
½aꢀD ¼ þ84:85 (c 1.98, DMSO). Found: C, 67.06; H, 6.81;
IR (ATR): 3337, 2948, 2864, 1616, 1519, 805 cmꢁ1 1H
.
N, 12.08. C13H16N2O2 requires C, 67.22; H, 6.94; N,
NMR (250 MHz, CDCl3, rt): d = 6.99 (d, 3J = 8.5 Hz,
1
3
12.06. IR (ATR): 3292, 3242, 1679, 1646, 1561 cmꢁ1. H
2 · CH), 6.58 (d, J = 8.5 Hz, 2 · CH), 3.95 (s, NH), 3.36
NMR (250 MHz, DMSO-d6, rt): d = 7.27 (m, 5 · CH),
7.22 (s, NH), 6.94 (d, 3J = 7.6 Hz, NH), 5.03 (m, CH),
4.13 (m, CH), 2.42/2.08 (m, CH2), 2.23 (m, COCH2),
1.47 (t, 3J = 6.9 Hz, CH3) ppm. 13C NMR (62.9 MHz,
DMSO-d6, rt): d = 179.5 (CO), 171.0 (CO), 142.9 (C),
2 · 128.7, 127.4, 2 · 126.1 (5 · CH), 57.1 (CH), 48.8
(CH), 29.3 (COCH2), 25.7 (CH2), 21.6 (CH3) ppm. MS
(EI, 70 eV): m/z (%) = 232 (10) [M+], 84 (100)
[MꢁC9H10NO]+.
(m, CH), 3.15/2.94 (m, CH2), 2.94 (m, CH2), 2.25 (s,
CH3), 1.90/1.46 (m, CH2), 1.80 (s, NH), 1.76 (m, CH2)
ppm. 13C NMR (62.9 MHz, CDCl3, rt): d = 146.3 (C),
129.7 (2 · CH), 126.5 (C), 113.2 (2 · CH), 57.7 (CH),
49.1 (CH2), 46.5 (CH2), 29.6 (CH2), 25.8 (CH2) 20.3
(CH3) ppm.
4.3.3.
2,4,6-Trimethyl-N-(pyrrolidin-2-ylmethyl)-aniline
3c.10 Yield 38.1%, bp 164 ꢁC/7.8 · 10ꢁ2 Torr (colour-
20
less oil). ½aꢀD ¼ þ23:25 (c 5.85, CHCl3). HRMS m/z
4.2.10. N-(S)-1-Phenylethyl-5-oxo-pyrrolidine-(S)-2-carbox-
amide 2i. Yield 81.7%, mp 134 ꢁC (white solid).
219.1844 [M+H]+. C14H23N2 requires 219.1861. IR
(ATR): 3336, 2945, 2914, 2864, 1484, 852 cmꢁ1 1H
.
20
½aꢀD ¼ ꢁ89:6 (c 2.21, DMSO). Found: C, 67.26; H, 6.92;
NMR (400 MHz, CDCl3, rt): d = 6.83 (s, 2 · CH), 3.33
(m, CH), 2.96 (m, CH2), 2.96/2.79 (m, CH2), 2.30 (s,
2 · CH3), 2.25 (s, CH3), 1.91/1.43 (m, CH2), 1.81/1.72
(m, CH2) ppm, NH protons were not detected. 13C NMR
(100 MHz, CDCl3, rt): d = 143.7 (C), 131.0 (C), 129.6
(2 · C), 129.4 (2 · CH), 58.9 (CH), 53.5 (CH2), 46.6
(CH2), 29.5 (CH2), 25.9 (CH2), 20.5 (CH3), 18.4
(2 · CH3) ppm.
N, 12.04. C13H16N2O2 requires C, 67.22; H, 6.94; N,
1
12.06. IR (ATR): 3296, 1707, 1648, 1528 cmꢁ1. H NMR
(250 MHz, DMSO-d6, rt): d = 7.27 (m, 5 · CH), 7.26 (s,
3
NH), 7.21 (d, J = 7.6 Hz, NH), 5.05 (m, CH), 4.02 (m,
CH), 2.38/2.11 (m, CH2), 2.22 (m, COCH2), 1.45 (t,
3J = 7.3 Hz, CH3) ppm. 13C NMR (62.9 MHz, DMSO-
d6, rt): d = 179.4 (CO), 171.2 (CO), 143.0 (C), 2 · 128.6,
127.4, 2 · 126.1 (5 · CH), 57.1 (CH), 48.9 (CH), 29.3
(COCH2), 25.6 (CH2), 21.7 (CH3) ppm. MS (EI, 70 eV):
m/z (%) = 232 (5) [M+], 84 (100) [MꢁC9H10NO]+.
4.3.4. 4-Chloro-N-(pyrrolidin-2-ylmethyl)-aniline 3d. Yield
70.7%, bp 160 ꢁC/6.5 · 10ꢁ2 Torr (yellow oil). 3d crystallize

1740
U. Ko¨hn et al. / Tetrahedron: Asymmetry 18 (2007) 1735–1741
after standing for several days at room temperature, mp
(CH), 52.3 (CH2), 46.1 (CH2), 29.4 (CH2), 25.4 (CH2),
24.2 (CH3) ppm.
20
143 ꢁC. ½aꢀD ¼ þ27:1 (c 2.58, CHCl3). HRMS m/z
211.1002 [M+H]+. C11H16N2Cl requires 211.1017. IR
(ATR): 3375, 3304, 2955, 2853, 1599, 814 cmꢁ1
.
1H
NMR (250 MHz, CDCl3, rt): d = 7.10 (d, 3J = 8.8 Hz,
4.3.9. (S)-1-Phenylethyl-(pyrrolidin-(S)-2-ylmethyl)-amine
3
2 · CH), 6.54 (d, J = 8.8 Hz, 2 · CH), 4.17 (s, NH), 3.36
3h.25 Yield 49.2%, bp 117 ꢁC/1.0 · 10ꢁ1 Torr (colour-
20
(m, CH), 3.12/2.89 (m, CH2), 2.92 (m, 2H, CH2), 1.90
(m, 2H, CH2), 1.84 (s, 1H, NH), 1.72 (m, 2H, CH2) ppm.
13C NMR (62.9 MHz, CDCl3, rt): d = 147.1 (C), 128.9
(2 · CH), 121.7 (C), 114.0 (2 · CH), 57.5 (CH), 48.6
(CH2), 46.5 (CH2), 29.5 (CH2), 25.8 (CH2) ppm.
less oil). ½aꢀD ¼ ꢁ15:3 (c 3.40, CHCl3). HRMS m/z
205.1703 [M+H]+. C13H21N2 requires 205.1705. IR
1
(ATR): 3343, 2958, 2867, 1450, 760, 700 cmꢁ1. H NMR
(250 MHz, CDCl3, rt): d = 7.25 (m, 2 · CH), 7.23 (m,
2 · CH), 7.13 (m, CH), 3.65 (q, 3J = 6.4 Hz, CH), 3.05
(m, CH), 2.78 (m, CH2), 2.32 (m, CH2), 2.27 (s, 2 · NH),
3
4.3.5. N-(Pyrrolidin-2-ylmethyl)-naphthalene-1-amine 3e.25
1.72/1.19 (m, CH2), 1.60 (m, CH2), 1.28 (d, J = 6.4 Hz,
Yield 64.1%, bp 220 ꢁC/7.2 · 10ꢁ2 Torr (brown yellow
CH3) ppm. 13C NMR (62.9 MHz, CDCl3, rt): d = 145.6
(C), 128.2 (2 · CH), 126.5 (CH), 126.3 (2 · CH), 58.2
(CH), 58.1 (CH), 52.3 (CH2), 46.1 (CH2), 29.4 (CH2),
25.4 (CH2), 24.2 (CH3) ppm.
20
oil). ½aꢀD ¼ þ52:0 (c 3.27, CHCl3). HRMS m/z 227.1536
[M+H]+. C15H19N2 requires 227.1548. IR (ATR): 3380,
1
3051, 2951, 2863, 1580, 766 cmꢁ1. H NMR (250 MHz,
CDCl3, rt): d = 7.97–6.57 (m, 7 · CH), 5.00 (s, NH), 3.55
(m, CH), 3.32/3.09 (m, CH2), 2.97 (m, CH2), 2.06 (s,
NH), 1.99/1.57 (m, CH2), 1.85/1.76 (m, CH2) ppm. 13C
NMR (62.9 MHz, CDCl3, rt): d = 143.9 (C), 134.3 (CH),
128.5, 126.6, 125.7, 124.6, 120.2, 117.2, 104.4 (7 · CH),
123.7 (C), 57.5 (CH), 48.6 (CH2), 46.6 (CH2), 29.8 (CH2),
25.9 (CH2) ppm.
4.4. X-ray crystallography
The intensity data for the compound were collected on a
Nonius KappaCCD diffractometer using graphite-mono-
chromated Mo-Ka radiation. Data were corrected for Lor-
entz, polarization effects and not for absorption effects.26,27
The structure was solved by direct methods (SHELXS28) and
refined by full-matrix least squares techniques against F o2
(SHELXL-9729). All the hydrogen atoms of 1 and the hydro-
gen atoms of the amine group and of the water molecules
of 3d were located by difference Fourier synthesis and
refined isotropically. All non-hydrogen atoms were
refined anisotropically.26 XP (SIEMENS Analytical
X-ray Instruments, Inc.) was used for structure
representations.
4.3.6. Benzyl-(pyrrolidin-2-ylmethyl)-amine 3f.10 Yield
20
47.0%, bp 198 ꢁC/4.0 · 10ꢁ2 Torr (colourless oil). ½aꢀD
¼
þ15:15 (c 5.81, CHCl3). HRMS m/z 191.1548 [M+H]+.
C12H19N2 requires 191.1536. IR (ATR): m 3314, 2954,
2869, 2813, 1452, 773 cmꢁ1. H NMR (250 MHz, CDCl3,
1
rt): d = 7.25–7.06 (m, 5 · CH), 3.68 (s, Ph–CH2), 3.10 (m,
CH), 2.76 (m, CH2), 2.50/2.42 (m, CH2), 1.70/1.23 (m,
CH2), 1.81–1.46 (s, 2 · NH), 1.58 (m, CH2) ppm. 13C
NMR (62.9 MHz, CDCl3, rt): d = 140.1 (C), 127.8
(2 · CH), 127.5 (2 · CH), 126.2 (CH), 57.8 (CH), 54.0
(CH2), 53.6 (CH2), 45.9 (CH2), 29.1 (CH2), 25.2 (CH2)
ppm.
Crystal data for 1:30 C7H6Cl3NO3, Mr = 258.48 g molꢁ1
,
colourless prism, size 0.10 · 0.10 · 0.10 mm3, orthorhom-
bic, space group P212121, a = 6.0396(2), b = 10.1568(4),
3
˚
˚
4.3.7. 4-Methylbenzyl-(pyrrolidin-(S)-2-ylmethyl)-amine 3g.
c = 15.5495(6) A, V = 953.85(6) A , T = ꢁ90 ꢁC, Z = 4,
Yield 34.1%, bp 140 ꢁC/6.5 · 10ꢁ2 Torr (colourless oil).
q
calcd. = 1.800 g cmꢁ3, l (Mo-Ka) = 9.37 cmꢁ1, F(000) =
20
½aꢀD ¼ þ14:95 (c 3.88, CHCl3). HRMS m/z 205.1712
520, 6815 reflections in h(ꢁ7/7), k(ꢁ13/13), l(ꢁ17/20),
[M+H]+. C13H21N2 requires 205.1705. IR (ATR): 3309,
measured in the range 2.40ꢁ 6 H 6 27.46ꢁ, completeness
1
2951–2817, 1514, 1452 cmꢁ1. H NMR (250 MHz, CDCl3,
Hmax = 99.9%, 2154 independent reflections, Rint = 0.0333,
3
3
rt): d = 7.18 (d, J = 8.0 Hz, 2 · CH), 7.09 (d, J = 8.0 Hz,
2 · CH), 3.73 (s, N–CH2), 3.20 (m, CH), 2.86 (m, CH2),
2.59/2.49 (m, CH2), 2.30 (s, CH3), 2.07 (s, 2 · NH), 1.81/
1.30 (m, CH2), 1.69 (m, CH2) ppm. 13C NMR
(62.9 MHz, CDCl3, rt): d = 137.3 (C), 136.2 (C), 128.8
(2 · CH), 127.9 (2 · CH), 58.2 (CH), 54.3 (CH2), 53.7
(CH2), 46.3 (CH2), 29.5 (CH2), 25.5, 20.9 (CH3) ppm.
1911 reflections with Fo > 4r(Fo), 151 parameters, 0
restraints, R1obs = 0.0287, wR2obs ¼0.0660, R1all = 0.0368,
wR2all ¼0.0696,
GOOF = 1.027,
0.06(7), largest difference peak and hole: 0.253/
Flack-parameter
ꢁ3
˚
ꢁ0.308 e A
.
Crystal data for 3d:30 C11H15ClN2 Æ 0.5H2O, Mr =
219.71 g molꢁ1
,
colourless prism, size 0.05 · 0.05 ·
4.3.8. (R)-1-Phenylethyl-(pyrrolidin-(S)-2-ylmethyl)-amine
0.05 mm3, orthorhombic, space group P212121, a =
3i.11 Yield 53.6%, bp 111 ꢁC/5.4 · 10ꢁ2 Torr (colourless
7.9859(2),
b = 13.5576(6),
c = 20.9296(8) A,
V =
˚
20
3
2266.04(14) A , T = ꢁ90 ꢁC, Z = 8, qcalcd. = 1.288 g cmꢁ3
,
˚
oil). ½aꢀD ¼ þ27:13 (c 2.58, CHCl3). HRMS 205.1708
m/z [M+H]+. C13H21N2 requires 205.1705. IR (ATR):
l (Mo-Ka) = 3.07 cmꢁ1, F(000) = 936, 19015 reflections in
h(ꢁ9/10), k(ꢁ17/16), l(ꢁ27/22), measured in the range
3304, 2959, 2868, 1450, 760, 669 cmꢁ1
.
1H NMR
(250 MHz, CDCl3, rt): d = 7.25 (m, 3 · CH), 7.16 (m,
1.79ꢁ 6 H 6 27.48ꢁ, completeness
Hmax = 99.7%, 5175
3
CH), 3.70 (q, J = 6.9 Hz, CH), 3.13 (m, CH), 2.77 (m,
independent reflections, Rint = 0.0401, 4203 reflections with
Fo > 4r(Fo), 286 parameters, 0 restraints, R1obs = 0.0449,
wR2obs ¼0.1105, R1all = 0.0614, wRa2ll ¼ 0:1205, GOOF =
1.023, Flack-parameter ꢁ0.04(7), largest difference peak
CH2), 2.46/2.24 (m, CH2), 2.23 (s, 2 · NH), 1.75/1.20 (m,
CH2), 1.59 (m, CH2), 1.29 (d, 3J = 6.9 Hz, CH3) ppm.
13C NMR (62.9 MHz, CDCl3, rt): d = 145.6 (C), 128.2
(2 · CH), 126.5 (CH), 126.3 (2 · CH), 58.2 (CH), 58.1
ꢁ3
˚
and hole: 0.194/ꢁ0.407 e A
.

U. Ko¨hn et al. / Tetrahedron: Asymmetry 18 (2007) 1735–1741
1741
3J = 8.8 Hz, 2H, 2 · CH), 5.83 (m, 2 · NH), 5.57 (m, 2H,
CH), 2.13 (s, 3H, CH3) ppm. 13C NMR (62.9 MHz, DMSO-
d6, rt): d = 144.0 (C), 129.3 (2 · CH), 126.2 (C), 113.6
(2 · CH), 104.6 (Cl3C), 75.7 (CH), 20.0 (CH3) ppm. Anal.
Calcd for C16H17Cl3N2: C, 55.92; H, 4.99; N, 8.15. Found: C,
55.81; H, 4.99; N, 7.92.
Acknowledgements
Financial support by the Deutsche Forschungsgemeins-
chaft (Sonderforschungsbereich 436), the Fond der Chem-
ischen Industrie (Germany) and by the Thuringer
Ministerium fur Wissenschaft, Forschung und Kultur (Er-
¨
furt, Germany) is gratefully acknowledged.
¨
16. Davies, A. G.; Kennedy, J. D. J. Chem. Soc. 1971, 68.
17. Crampton, M. R.; Lord, S. D.; Millar, R. J. Chem. Soc.,
Perkin Trans. 2 1997, 909.
18. HPLC conditions: column Chiralcel-OD–H, Compound 3a:
n-hexane/i-propanol (80:20), butylamine (0.1%), detection
wavelength 250, 0.6 ml/min, temperature 30 ꢁC. Compound
3b: n-hexane/i-propanol (95:5), butylamine (0.1%), detection
wavelength 250, 0.6 ml/min, temperature 30 ꢁC. Compound
3c: n-hexane/i-propanol (99.3:0.7), butylamine (0.1%), detec-
tion wavelength 250, 0.6 ml/min, temperature 40 ꢁC. Com-
pound 3d: n-hexane/i-propanol (98:2), butylamine (0.2%),
detection wavelength 250, 1.0 ml/min, temperature 40 ꢁC.
Compound 3e: n-hexane/i-propanol (60:40), butylamine
(0.1%), detection wavelength 250, 0.6 ml/min, temperature
30 ꢁC. Compound 3f: n-hexane/i-propanol (98:2), butylamine
(0.5%), detection wavelength 267, 0.8 ml/min, temperature
40 ꢁC. Compound 3g: n-hexane/i-propanol (98:2), butylamine
(0.5%), detection wavelength 253, 0.6 ml/min, temperature
30 ꢁC. Compound 3h: n-hexane/i-propanol (99.7:0.3), butyl-
amine (0.5%), detection wavelength 245, 0.3 ml/min, temper-
ature 45 ꢁC. Compound 3i: n-hexane/i-propanol (99.3:0.7),
butylamine (0.5%), detection wavelength 245, 0.6 ml/min,
temperature 40 ꢁC.
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