Internal coordination and solvent effects upon hetero- and homocomplexation of chiral lithium amides: Structure reactivity effects

Article abstract of DOI:10.1016/S0022-328X(00)00365-X

The two chiral lithium amides prepared from (R)-(2-N,N-dimethylamine-ethyl)-(1-phenyl-2-pyrrolidin-1-yl-ethyl)amine (1) and (R)-(2-methoxyethyl)-(1-phenyl-2-pyrrolidin-1-yl-ethyl)amine (2) and n-BuLi, were found to form symmetrically solvated dimers in di

Full text of DOI:10.1016/S0022-328X(00)00365-X

www.elsevier.nl/locate/jorganchem
Journal of Organometallic Chemistry 608 (2000) 153–163
Internal coordination and solvent effects upon hetero- and
homocomplexation of chiral lithium amides: structure reactivity
effects
8
Anna Johansson, Anders Pettersson, Ojvind Davidsson *
Department of Organic Chemistry, Go¨teborg Uni6ersity, SE-412 96 Go¨teborg, Sweden
Received 27 December 1999; accepted 9 May 2000
Abstract
The two chiral lithium amides prepared from (R)-(2-N,N-dimethylamine-ethyl)-(1-phenyl-2-pyrrolidin-1-yl-ethyl)amine (1) and
(R)-(2-methoxyethyl)-(1-phenyl-2-pyrrolidin-1-yl-ethyl)amine (2) and n-BuLi, were found to form symmetrically solvated dimers
in diethylether (DEE). The addition of tetrahydrofuran (THF) and of 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone
6
(DMPU) did not affect the Li-NMR chemical shift due to a very strong internal coordination. Their reactivity as chiral bases
in the desymmetrization of cyclohexenoxide was very low due to this strong entropy driven internal coordination. However, they
were found to easily form mixed complexes with n-BuLi which was verified by 13C-NMR and 6Li, 1H-HOESY NMR. One
molecule of n-BuLi and one molecule of the chiral lithium amide Li-1 respectively Li-2 constituted the mixed complexes. In this
mixed dimer at least one coordination site is available on lithium for coordination of the substrate. The alkylation of
benzaldehyde using Li-1/n-BuLi gave 40% and Li-2/n-BuLi gave 30% enantiomeric excess of the (S)-1-phenyl-1-pentanol in very
high chemical yields. © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Chiral lithium amides; HOESY-NMR; Internal coordination; Mixed complexes; Alkylation; Deprotonation
gates [3]. To the best of our knowledge there exist only
a few X-ray crystallographic studies [4] and NMR
spectroscopic studies [5] on chiral n-BuLi complexes.
Recently it has been shown that mixed complexes be-
tween chiral lithium amides and alkyllithium reagents
can be used with great success in the formation of
stereogenic carbon atoms [6]. The molecular design of
chiral auxiliaries and ligands for use in asymmetric
synthesis is one important task of modern organic
chemistry. A variety of chiral ligands have been de-
signed for catalytic or stoichiometric chirality transfer
in various reactions [7].
1. Introduction
Nucleophilic addition to carbonyl carbon atoms us-
ing organometallic reagents, e.g. R2Zn, RMgX, RCu,
and the use of organolithium bases in deprotonation
reactions are central reactions in organic synthesis to-
day [1]. The addition reactions provide a reliable route
to optically active secondary alcohols, when chiral aux-
iliaries or ligands are used. Despite the wide use of
organolithium reagents in organic synthesis, only a few
examples of asymmetric alkylation reactions using
alkyllithium reagents and non-covalently bound chiral
additives have been reported, compared to the more
investigated asymmetric deprotonation reactions [2].
One reason for the limited exploration of organolithium
reagents in addition reactions could be their high reac-
tivity and propensity to form homo- and hetero-aggre-
2. Result and discussion
In our development of chiral ligands to be used in
both asymmetric additions and deprotonation reactions
we obtained some intriguing results with respect to
solvent effects and the importance of internal coordina-
tion upon reactivity and selectivity. Previous studies of
* Corresponding author. Tel.: +46-31-7722901; fax: +46-31-
7723840.
E-mail address: ojvind.davidsson@oc.chalmers.se (O. Davidsson).
8
0022-328X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(00)00365-X

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A. Johansson et al. / Journal of Organometallic Chemistry 608 (2000) 153–163
chiral lithium amides with one internal coordinating
group gave dimers in diethylether (DEE) and tetrahydro-
furan (THF). By the introduction of an additional
internal coordinating group we expected to obtain
monomers in DEE and THF which would result in a
more reactive reagent [8]. The chiral amines (R)-(2-N,N-
dimethylamine - ethyl) - (1 - phenyl - 2 - pyrrolidin - 1 - yl-
ethyl)amine (1) and (R)-(2-methoxy-ethyl)-(1-phenyl-2-
pyrrolidin-1-yl-ethyl)amine (2) were prepared using the
method developed by O’Brien [9].
lents, was also found to have no effect upon the chemical
shift of the signal at l 2.35. The same observation, lack
of solvent effects upon chemical shifts, was also found
for the two signals at l 2.15 and 2.54. There was no
difference in intensity observed between the three signals
upon addition of THF or DMPU. The absence of solvent
effects upon chemical shifts is not in concordance with
our previous studies on chiral lithium amides with
internal coordination, where large chemical shift ranges
in the 6Li-NMR spectra were observed. Instead we
6
observed large chemical shift changes in the Li-NMR
spectra when e.g. THF was added. In our previous
studies of chiral lithium amides we obtained symmetri-
cally and unsymmetrically solvated dimers if DEE and
THF were used [11]. We interpret the observation of one
large signal at l 2.35 for the lithium salt of 1 (Li-1) to
be due to the formation of an internal symmetrically
coordinated dimer.
The 6Li-NMR spectra of the mixture of 1 (0.24 mmol)
and n-BuLi (0.24 mmol) in 0.7 ml diethylether (DEE-d10)
at −60°C showed the presence of one major signal at
l 2.35. Two very small peaks were also observed in a 1:1
ratio at l 2.15 and 2.54, respectively (Fig. 1a).
The addition of tetrahydrofuran (THF-d8) to the
above solution did not alter the chemical shift for the
large peak at l 2.35 even if up to five equivalents of THF
were added. Addition of 1,3-dimethyl-3,4,5,6-tetrahy-
dro-2(1H)pyrimidinone (DMPU) [10], up to 3.5 equiva-
Fig. 1. 6Li-NMR in DEE-d10 at −60°C of (a) Li-1, (b) Li-2.

A. Johansson et al. / Journal of Organometallic Chemistry 608 (2000) 153–163
155
was obtained. This shows that the cyclohexene oxide
does not or hardly coordinates to Li-1. The Li-NMR
The internal coordination results in two tetracoordi-
nated lithiums in the dimer, which is the most favorable
coordination state for lithium cations. The formation of
a monomer would result in three-coordinated lithium,
which would be more accessible for coordination of an
external coordinating solvent. Furthermore, the T1 re-
6
spectra of the mixture of 2 (0.24 mmol) and n-BuLi
(0.24 mmol) in 0.7 ml diethylether (DEE) at −60°C
showed the presence of only one large signal at l 2.20
(Fig. 1). The effect on the 6Li-NMR spectra upon
addition of THF and DMPU was the same as found
for Li-1. The desymmetrization reaction using the
lithium salt of 2 (Li-2) gave a similar result as found for
Li-1 with less than 5% conversion after 48 h and no
enantiomeric excess was obtained. All these observa-
tions are in agreement with our NMR studies showing
that additives, solvents and consequently substrates do
not coordinate to the lithiums in Li-1 or Li-2 and
therefore the reaction rate is slow with no stereoselec-
tivity. The 13C-NMR spectrum showed only one set of
13C-NMR signals indicating that only one species is
present in the solution.
6
laxation of the Li-NMR peak at l 2.35 of 7.9 s is in
the range for a dimeric complex rather than a monomer
or higher aggregates such as trimers and tetramers [12].
The two small peaks at l 2.15 and 2.54 with T1
relaxation times of 9.5 and 10.3 s, respectively, appear-
ing in a 1:1 ratio, we interpret as originating from an
internal non-symmetrically solvated dimer. However
both lithiums are still tetra-coordinated.
Geometry optimization calculations of Li-1 and Li-2
using the semi-empirical PM3 method showed that the
most stable geometry, by 15 kcal mol−1, was the one
where each lithium in the dimer coordinates one pyrro-
lidin nitrogen and one methoxy oxygen in Li-2 [13]. The
difference in energy between the dimer where each
lithium coordinates one pyrrolidin and one dimethyl
nitrogen compared to the dimer where one lithium
coordinates two pyrrolidin nitrogens and the other
coordinates two dimethyl nitrogens was only 9 kcal
mol−1 in favor of the first. This also explains why a
small amount of the non-symmetrically solvated dimer
The addition of an excess of n-BuLi to a sample of
Li-1 and Li-2, respectively, in DEE at −60°C gave rise
6
to three new signals in each case. The Li-NMR of Li-1
and n-BuLi in excess (two equivalents) gave two signals
at l 2.26 and 2.53 with T1 relaxation times of 9.5 and
10.3 s, respectively. These two signals were found to
appear in a 1:1 ratio. The 6Li-NMR of Li-2 and n-BuLi
in excess (three equivalents) also gave two new signals
at l 2.03 and 2.46. These two signals were found to
appear in a 1:1 ratio (Fig. 2).
6
is observed in the Li-NMR spectra.
Based upon observed T1 relaxation times of the two
signals at l 2.26 and 2.53, from Li-1 with an excess of
n-BuLi added, we tentatively assigned these to originate
from the heterocomplex Li-1/n-BuLi. The same inter-
pretation was also made for Li-2 with an excess of
n-BuLi added.
The use of Li-1 in the desymmetrization of cyclohex-
ene oxide also showed that the internal coordination is
strong. In a sample constituted of 0.126 mmol of Li-1
and 0.180 mmol of cyclohexenoxide in DEE, the yield
of the corresponding allylic alcohol was found to be
less than 5% after 200 h and no enantiomeric excess
A third signal was also observed at l 1.90 with a T1
relaxation time of 14 s. The signal at l 1.90 was

156
A. Johansson et al. / Journal of Organometallic Chemistry 608 (2000) 153–163
Fig. 2. 6Li-NMR in DEE-d10 at −60°C of (a) Li-1 with two equivalents of n-BuLi in excess, (b) Li-2 with three equivalents of n-BuLi in excess.
6
NOE effects to Li-2 protons. A
6Li, Li-EXSY NMR
tentatively assigned to the homocomplex [n-BuLi]4
based upon T1 relaxation time and the fact that this
signal increased upon addition of n-BuLi. The 6Li,
1H-HOESY spectra of the above solution unequivocally
showed that the two new signals, trace at l 2.26 and
2.53, indeed originate from the heterocomplex Li-1/n-
BuLi as NOE effects were observed between both the
Li-1 and the methylene a-protons at l −1.1 and −1.2
in n-BuLi (Fig. 3).
Interestingly the two methylene a-protons from the
complexed n-BuLi display different chemical shifts.
They are diastereotopic, due to nearby inherent chiral-
ity. In contrast the trace at l 2.35, previously assigned
to originate from the homodimer Li-1, only showed
NOE effects to Li-1 protons. Finally the trace at l 1.90
assigned to homocomplexed n-BuLi tetramer only
showed NOE effects to one set of methylene a-protons
on n-BuLi at l −1.0 and not to any Li-1 protons. The
same pattern was also seen using Li-2 and an excess of
n-BuLi (three equivalents) where the traces at l 2.03
and 2.46 showed NOE effects to both the Li-2 protons
and to two diastereotopic methylene a-protons at l
−1.0 and −1.2 from n-BuLi (Fig. 4).
spectrum also showed an exchange between the lithium
signals at l 2.03 and 2.46 indicating that they originate
from one and the same complex. No other correlations
were observed (Fig. 5).
By using the 6Li, 1H-HOESY experiment we were
able to assign all new species formed and to assign
which lithium is coordinated to which internal coordi-
nating group. The trace at l 2.26 from Li-1/n-BuLi
shows a strong NOE to the phenyl ring protons; this
NOE correlation is not seen in the trace at l 2.53.
Based upon geometries obtained from semiempirical
PM3 calculations we are able to assign the lithium
signal appearing at l 2.26 to be internally coordinated
with the –N(CH3)2 nitrogen. The phenyl proton lithium
,
distances are 2.5 A to the lithium coordinating with the
–N(CH3)2 nitrogen and 3.7 A to the lithium coordinat-
ing with the pyrrolidin nitrogen. The mixed complex
Li-2/n-BuLi also showed significant differences in NOE
correlations to the phenyl ring protons. The phenyl
proton lithium distances are 2.8 A to the –OCH3
oxygen coordinated lithium and 3.9 A to the pyrrolidin
nitrogen coordinated lithium. Based upon the semiem-
pirical PM3 calculated geometries we are able to assign
the lithium signal appearing at l 2.03 to the lithium
that is internally coordinated with the –OCH3 oxygen.
,
,
,
The trace at l 1.83 showed NOE effects to the
a-protons in n-BuLi at l −1.1 but not to any Li-2
protons and finally the trace at l 2.20 showed only

A. Johansson et al. / Journal of Organometallic Chemistry 608 (2000) 153–163
157
The 13C-NMR spectrum also showed that a mixed
dimer was formed, as two sets of carbon signals were
seen, one set from the chiral lithium amide homodimer
In an analogous manner the pyrrolidin ring protons for
,
the complex Li-2/n-BuLi have distances of 5.0 A to
,
lithium at l 2.26 and 2.8 A to the lithium at l 2.53.
Fig. 3. 6Li, 1H-HOESY NMR in DEE-d10 at −60°C for Li-1 with two equivalents of n-BuLi in excess showing the 6Li-NMR traces at l 1.90,
2.26, 2.35, and 2.53 ppm.

158
A. Johansson et al. / Journal of Organometallic Chemistry 608 (2000) 153–163
Fig. 4. 6Li, 1H-HOESY NMR in DEE-d10 at −60°C for Li-2 with three equivalents of n-BuLi in excess showing the 6Li-NMR traces at l 1.83,
2.03, 2.20, and 2.46 ppm.

A. Johansson et al. / Journal of Organometallic Chemistry 608 (2000) 153–163
159
3. Summary
and one set from the chiral lithium amide/n-BuLi
heterocomplex.
Furthermore, the 13C-NMR spectrum of the above
solutions of Li-1 and Li-2 displayed two carbanionic
carbons each, for Li-1 at l 15.9 and 14.0 and for
Li-2 at l 15.5 and 14.0. Different coupling patterns
were observed as different coupling magnitudes (Fig.
6).
The signals at l 15.9 and 15.5 displayed a pentet
with a carbon–lithium coupling of 8.2 and 8.3 Hz,
respectively. The two signals at l 14.0 displayed a
septet with a carbon–lithium coupling around 5.3 Hz.
Both the magnitudes and the multiplicities of the
lithium–carbon couplings show that the carbon sig-
nals at l 15.9 and 15.2 originate from the mixed
complexes Li-1/n-BuLi and Li-2/n-BuLi, respectively.
The two carbon signals at l 14.0 originate from n-
BuLi homotetramers.
The ability of Li-1 and Li-2 to coordinate n-BuLi
was determined by measuring the relative 6Li-NMR
intensities. The equilibrium complexation constant for
Li-1 to coordinate n-BuLi was found to be K=1.8
M−1 and for Li-2 K=49 M−1 at −60°C. The
higher complexation constant for Li-2 to n-BuLi is
also reflected in the 13C-NMR spectra (Fig. 6).
The butylation of benzaldehyde was investigated
using Li-1 and Li-2 with a slight excess of n-BuLi
(1.4 equivalents) with respect to amine. The mixed
complex Li-1/n-BuLi gave, upon reaction with ben-
zaldehyde, an enatiomeric excess of 40% of the (S)-1-
With this study we have shown that the role of
internal coordination, and the coordination number
obtained, largely affects the reactivity of the reagent.
In the case of using the amines as chiral bases one
should avoid using amines exhibiting two potentially
internal coordinative groups. The reason for this is
that there will be no coordination site available for
the substrate, the two lithiums are tetracoordinated.
The internal coordination seems to be very strong
probably due to favorable entropy. The mixed dimer
has at least one coordinating site available at each
lithium for coordination of benzaldehyde. This is
reflected in the enantiomeric excess and chemical yield
obtained. The enantiomeric excess is not as high as in
previous reports but we see a large potential in using
these amines as two chirality centers can be intro-
duced, one at each lithium internal coordinating link.
4. Experimental
4.1. General
All glassware used for synthesis was dried
overnight in a 120°C oven when necessary. Glassware
and syringes used for the NMR studies and alkyla-
tion reactions were dried at 50°C in a vacuum oven
before transfer into a glove box (Mecaplex GB 80
equipped with a gas purification system that removes
oxygen and moisture) containing a nitrogen atmo-
sphere. Typical moisture content was less than 0.5
ppm. Most manipulations concerning the alkylation
reactions were carried out in the glove box using gas-
tight syringes. Ethereal solvents, distilled under nitro-
phenyl-1-pentanol
and
Li-2/n-BuLi
gave
an
enantiomeric excess of 30% of the (S)-1-phenyl-1-pen-
tanol. These observations are all in agreement with
our NMR studies showing that a mixed complex is
formed that transfers its chirality in the reactions to
give enatiomeric enriched products.
Fig. 5. 6Li, 6Li-EXSY NMR in DEE-d10 at −60°C for Li-2 with three equivalents of n-BuLi in excess showing the correlations between signals
at l 2.03 and 2.46 ppm from the n-BuLi/Li-2 mixed complex.

160
A. Johansson et al. / Journal of Organometallic Chemistry 608 (2000) 153–163
Fig. 6. 13C-NMR in DEE-d10 at −60°C of (a) Li-1 with two equivalents of n-BuLi in excess showing the a-carbon signals from complexed
1
1
n-BuLi, at l 15.9 ppm (pentet, JCLi=8.2 Hz), and free n-BuLi, at l 14.0 ppm (septet, JCLi=5.3 Hz), respectively. (b) Li-2 with two equivalents
1
of n-BuLi in excess showing the a-carbon signals from complexed n-BuLi, at l 15.5 ppm (pentet, JCLi=8.3 Hz), and free n-BuLi, at l 14.0 ppm
(septet, 1JCLi=5.2 Hz), respectively.
gen from sodium and benzophenone, were kept over 4
Chromatographic analyses were carried out using a
Varian Star 3400 CX gas chromatograph. All GC
analyses were run on a chiral stationary phase column
(CP-Chirasil-DEX CB, 25 m, 0.32 mm) from
Chrompack. All analyses were done at 135°C (injector
225°C, detector 250°C) using He (2 ml min−1) as
carrier gas. Alkylation reaction analyses were per-
formed at 125°C and the epoxide opening reaction
analyses at 90°C. Mass spectra (MS) were recorded on
a Varian Saturn 2000 GC-MS/MS operating in elec-
tronic ionization (EI) or chemical ionization (CI) mode.
,
A molecular sieves in a septum sealed flask inside the
glove box. The concentrations of commercially avail-
able n-BuLi solutions (n-BuLi 1.6 M or 2.5 M solution
in hexanes, Aldrich) were determined by double Gilman
titration [14]. The enantiomeric purities of the synthe-
sized chiral amines were \95% enantiomeric excess.
1
Routine 1D H and 13C-NMR spectra were recorded
6
using a Varian Unity 400 MHz instrument. 1D Li and
6
1
6
6
2D Li, H-HOESY and Li, Li-EXSY spectra were
recorded using a Varian Unity 500 MHz instrument.

A. Johansson et al. / Journal of Organometallic Chemistry 608 (2000) 153–163
161
Methane was used as reagent gas for CI operation. The
GC column connected to the mass analyzer was a
DB-5MS (J&W Scientific).
added together with ethanol (50 ml) and water (5 ml). The
resulting mixture was vigorously stirred. After 48 h, water
(100 ml) was added, and the layers were separated. The
yellow aqueous layer was evaporated under reduced
pressure and was then extracted with ether (4×50 ml).
The combined organic phases were washed with 5%
aqueous sodium hydrogen carbonate (200 ml) and water
(200 ml), dried over sodium sulfate, filtrated. The solvent
was evaporated under reduced pressure to give the crude
product as a yellow oil which was purified by distillation
to give the pure product (4.01 g, 39%) as a colorless oil,
b.p. 120–125°C at 0.1 mmHg.
4.2. Synthesis
4.2.1. (R)-(2-N,N-Dimethylamine-ethyl)-(1-phenyl-2-
pyrrolidin-1-yl-ethyl)amine (1)
Pyrrolidine (7.26 g, 0.1 mol) was added to a 500 ml
round-bottled flask with ethanol (150 ml). (R)-styrene
oxide (5.7 g, 47.51 mmol) was added to the solution and
the solution was heated to reflux for 3 h. The solvent was
evaporated and the crude product was dried for 1 h under
high vacuum. The crude product was solvated in dry DEE
(100 ml) and triethyl amine (14.42 mg, 0.143 mol) was
added. The solution was cooled in an ice-bath and
methanesulfonyl chloride (6.56 g, 57.2 mmol) was added
dropwise via a syringe. The solution was stirred for 30
min and then triethylamine (9.62 g, 95 mmol) was added.
The solution reached room temperature and 25 equiva-
lents of N,N-dimetylethylenediamine (105 g, 1.18 mol)
and water (25 ml) were added. The solution was stirred
for 3 days. More water (50 ml) was added until the
two-layer solution became clear. The solution was swirled
for 5 h. The organic phase was removed and the
water-phase was extracted three times with DEE (3×50
ml). The combined ether phases were washed with
NaHCO3(5%, 50 ml) and water (50 ml) and dried over
Na2SO4. The solvent was evaporated. The product, a clear
light yellow oil, was purified by distillation under high
vacuum at 103°C at 3.3×10−2 mBar at a yield of 62%
(7.7 g, 29.5 mmol).
1
(400 MHz; CDC13); H-NMR (293 K) l 7.30–7.16
ppm (5H, m, Ph), 3.65 ppm (1H, dd, PhCHNH2),
3.41–3.35 ppm (2H, m, CH2OCH3), 3.26 ppm (3H, m,
OCH3),2.77 ppm (1H, t, CH2N), 2.62–2.51 ppm (4H, m,
NHCH2O, CH2N), 2.60–2.54 ppm (2H, in, CH2N), 2.20
ppm (1H, dd, CH2N), 1.77–1.69 ppm (4H, m, CH2CH2).
4.2.3. Epoxide opening
THF (803 ml) was added to a reaction vessel followed
by addition of the amine (32.9 ml, 0.126 mmol) under
nitrogen atmosphere. A solution of n-BuLi in hexane (74
ml, 0.17mmol)wasaddedandthereactionwasmaintained
at 20°C for 15 min. A solution of cyclohexene oxide in
THF (90 ml, 0.18 mmol) was added and the reaction
started. The reaction was monitored by extracting a small
portion of the reaction mixture. The samples were
quenched as follows. To a vial a sample of the reaction
mixture (100 ml) was added and the vial was filled with
dry DEE (0.5 ml). NH4Cl (0.5 ml) was added to the vial
and the lower phase was extracted. Brine (0.5 ml) was
added and the lower phase was extracted. The organic
phase was dried over NaSO4, and the organic phase was
transferred to a new vial equipped with septa. The
products were analyzed using chiral stationary phase GC.
1
(500 MHz; DEE-d10); H-NMR (293 K) l 7.36 ppm
(2H, d, Ph), 7.22 ppm (2H, t, Ph), 7.13 ppm (1H, t, Ph),
3.69 ppm (1H, dd, CH), 2.70 ppm (1H, t, CHCH2N), 2.62
ppm (4H, m, pyrrolidine), 2.48 ppm (4H, m, pyrrolidin),
2.42 ppm (2H, dd, NHCH2CHN(CH3)2), 2.23 ppm (2H,
dd, NHCH2CH2N(CH3)2), 2.16 ppm (1H, t, CHCH2N),
2.14 ppm (6H, s, N(CH3)2), 1.74 ppm (4H, dd, pyrro-
lidine).
4.2.4. Alkylation of benzaldehyde
A reaction flask containing a magnet, a dry 1:1
DMM:DEE solution (1.6 ml) and amine (0.20 mmol) was
prepared inside the glovebox. The flask was taken out and
fitted with a dry nitrogen inlet. The flask was cooled to
0°C and n-BuLi (0.28 mmol) was added via a syringe to
the stirred solution. After 15 min the flask was moved
to an ether/N2 (l) bath (−116°C). Benzaldehyde (0.05
mmol, as a 25% solution in DMM:DEE 1:1) was added
via a syringe and after 15 min the reaction was quenched
with methanol (0.5 ml). The crude mixture was analyzed
using chiral stationary phase GC.
4.2.2. (R)-(2-Methoxy-ethyl)-(1-phenyl-2-pyrrolidin-
1-yl-ethyl)amine (2)
To a stirred solution of pyrrolidine (5.6 ml, 68.1 mmol)
in ethanol (100 ml), was added (R)-styrene oxide (4.9 ml,
41.6 mmol) and the mixture was refluxed for 2 h. After
cooling, the solvent was evaporated under reduced pres-
sure. The crude product was given as slightly yellow oil,
which was dried under vacuum, and the product crystal-
lized. The crystals were dissolved in dry ether (100 ml)
and triethyl amine (17.4 ml, 124.8 mmol) was added and
the mixture was cooled to 0°C. Methanesulfonyl chloride
(3.9 ml 49.9 mmol) was added dropwise and a white
precipitate was formed. After 1 h triethylamine (11.6 ml,
83.2 mmol) was added and the mixture was allowed to
warm to room temperature. 2-Methoxyethylamine was
Acknowledgements
The authors are most grateful to Dr Gunnar Stenhagen,
Chalmers University Organic Chemistry, for mass spec-
tral analyses and the Swedish Natural Science Research
Council and Carl Trygger for financial support.

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A. Johansson et al. / Journal of Organometallic Chemistry 608 (2000) 153–163
J. Am. Chem. Soc. 107 (1985) 1810. (k) P.G. Williard, Carban-
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.