Synthesis and application of ligands for the asymmetric addition of organolithium reagents to imines

Article abstract of DOI:10.1039/a702028g

Amino acid derived ligands 4d,e are prepared from (S)-valine and (S)-proline respectively, and can be used as chiral ligands during the asymmetric addition of organolithium reagents to N-arylimines. Ligand 4e, which is prepared by two independent routes, is found to induce addition of organolithium reagents to the si-face of the imines, whilst ligand 4d in common with the previously reported catalysts 4a-c induces addition to the re-face of the imines.

Full text of DOI:10.1039/a702028g

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Synthesis and application of ligands for the asymmetric addition of
organolithium reagents to imines
Catrin A. Jones, Iwan G. Jones, Mushtaq Mulla, Michael North*,†
and Lucia Sartori
Department of Chemistry, University of Wales, Bangor, Gwynedd, UK LL57 2UW
Amino acid derived ligands 4d,e are prepared from (S)-valine and (S)-proline respectively, and can be used
as chiral ligands during the asymmetric addition of organolithium reagents to N-arylimines. Ligand 4e,
which is prepared by two independent routes, is found to induce addition of organolithium reagents to the
si-face of the imines, whilst ligand 4d in common with the previously reported catalysts 4a–c induces
addition to the re-face of the imines.
dentate ligands, with examples of good and not so good asym-
Introduction
metric induction being reported in both cases. The catalytic,
asymmetric addition of organometallic reagents to N-
heteroatom substituted imines7,11 and to nitrones12 has also
been reported.
An attractive feature of this chemistry is the large number of
natural products which contain a stereocentre adjacent to an
amino group, and in particular by the ease with which enantio-
merically pure allylic amines can be converted into α-amino
acids, α-amino aldehydes, β-amino acids, β-lactams and β-
amino alcohols (Scheme 1). However, catalysts 1–5 all suffer
In recent years, considerable progress has been made in the
asymmetric addition of carbon nucleophiles to prochiral car-
bonyl compounds under the influence of a chiral catalyst. In
particular, the asymmetric catalysis of the addition of cyanide1
(from hydrogen cyanide or trimethylsilyl cyanide) and the add-
ition of organozinc reagents2 to aldehydes and ketones have
both been achieved with excellent asymmetric induction. By
comparison, the asymmetric addition of carbon nucleophiles to
prochiral imines leading to optically active amines is a field
which is still in its infancy.3 A number of chiral auxiliary based
approaches have been reported,4 but reports of asymmetric
catalysts for this reaction are scarce. Compared to additions to
carbonyl compounds, a number of additional factors need to be
considered in the asymmetric addition of nucleophiles to
prochiral imines. These include the lower electrophilicity of the
carbon–nitrogen double bond compared to the carbonyl bond,
the electronic and steric nature of the substituent on the nitro-
gen atom, and the possibility of E,Z-isomerism about the
carbon–nitrogen double bond. The first of these factors can be
an advantage, as the uncatalysed addition of nucleophiles to an
imine will be retarded, but the second two points are
complications.
NHR1
R3
NHR1
R3
O
COOH
NHR1
R3
NR1
NHR1
R3
R3Li–cat*
HOOC
O
R2
R2
NHR1
R3
P
N
Very recently, the first report of a catalytic, asymmetric
Strecker reaction (addition of HCN to an imine) was reported,5
and there are a handful of reports of catalysts for the addition
of organolithium reagents to imines and their derivatives.
In particular, sparteine6,7 1, bis-oxazolines6 2, O,OЈ-
dialkyldihydrobenzoins8,9 3 and amino ethers8–10 4, 5 have been
employed as chiral catalysts and/or chiral ligands for this reac-
tion. It is notable that structures 1–5 include both bi- and tri-
OH
R3
Scheme 1
from one or more disadvantages as chiral catalysts, these
include the availability of only one enantiomer, low levels of
asymmetric induction, the need to use stoichiometric or greater
amounts of the chiral species, and narrow substrate specificity.
Thus, a research programme aimed at the development of more
versatile catalysts for the asymmetric addition of organolithium
reagents to imines was initiated within our group. In this paper,
we report details of our results on the design of ligands
analogous to compounds 4 for the asymmetric addition of
organolithium reagents to α,β-unsaturated imines.13
H
R1
R1
H
N
R1
R2O
R1
O
O
N
H
N
N
OR2
R2
R2
H
1
2
3
Synthesis of chiral ligands
R
Of the chiral ligands 1–5, those represented by structure 4
appeared to be a suitable starting point for our work. These
ligands are readily prepared from (S)-amino acids and offer
great scope for variation during optimisation studies. Three
such catalysts 4a–c have previously been reported,8–10 each of
which induces the addition of an organolithium reagent (methyl-
lithium, butyllithium or vinyllithium) to the re-face of an N-
(p-methoxyphenyl)imine as shown in Scheme 2. Ligands 4a–c
O
O
Me2N
Me2N
R
MeO
MeO
5
4
† E-mail: m.north@bangor.ac.uk.
J. Chem. Soc., Perkin Trans. 1, 1997
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OMe
R2
O
Me2N
R
NHAr
MeO
H
R1
4a R2 = CH2Ph
b R2 = Ph
c R2 = CH2CMe3
R–Li+
N
R1
R = Me, Bu, H2C=CH
R1 = Ph, PhCH=CH, 1-Naph, 2-Naph
Scheme 2
have been investigated in both stoichiometric (2.6 equiv.) and
catalytic (0.05–0.3 equiv.) quantities, with higher enantiomeric
excesses being obtained in the former case (42–77% versus 25–
64%).
We decided to investigate the effect of further variation in the
structure of the ligands, and chose to prepare ligands 4d derived
from (S)-valine, and 4e derived from (S)-proline. Ligand 4d
offered the opportunity to investigate the effect of steric influ-
ences on the activity of the catalyst, whilst ligand 4e being
derived from a cyclic, secondary amino acid was anticipated to
have fewer available conformations.
The synthesis of ligands 4d,e was initially achieved from the
corresponding amino acids using the route previously reported
for ligands 4a,c9,14 as shown in Scheme 3. Thus reaction of (S)-
R1
R1
R2
R2
OH
i
N
H
COOH
N
H
37–69%
Fig. 1 13C NMR spectra of a mixture of compounds 4e and 11
recorded at ϩ55 ЊC (a), ϩ20 ЊC (b) and Ϫ50 ЊC (c)
6a R1 = CHMe2, R2 = H
b R1–R2 = CH2CH2CH2
7a,b
timescale. The former possibility appeared quite likely, since the
final step of the synthesis will proceed via the aziridinium salt
10 as shown in Scheme 4. Ring opening of the aziridinium ring
ii
84–98%
R1
R1
9b
R2
OH
iii
R2
Cl
N
Me
N
Me
61–77%
9a,b
8a R1 = CHMe2, R2 = Me
b R1–R2 = CH2CH2CH2
O
O
ring
open
at Cb
ring
open
at Ca
b
a
N
Me
41–87% iv
N
N
Me
MeO
MeO
Me
4e
10
11
R1
Scheme 4
R2
O
N
Me
of compound 10 could occur at two sites, leading to com-
pounds 4e and 11 respectively. A variable temperature 13C
NMR study [Ϫ50 to ϩ55 ЊC Fig. 1(a)–(c)] showed that both the
intensities and the chemical shifts of the 13C resonances were
temperature dependent. The changes in intensity of the peaks
are quite noticeable in Fig. 1, and the largest change in chemical
shift (2.0 ppm) is seen for the resonance corresponding to the
CH2O, which occurs at 70.6 ppm at Ϫ50 ЊC but at 72.6 ppm at
ϩ50 ЊC. This information strongly suggested that the appear-
ance of multiple peaks in the NMR spectra of compound 4e
was due to the presence of two rotamers, as did the fact that
capilliary GC analysis of compound 4e gave a single peak.
To further investigate the possible presence of compound 11,
an alterative synthesis of catalyst 4e was developed as shown in
Scheme 5. Thus reduction of N-benzyloxycarbonylproline gave
N-benzyloxycarbonylprolinol 12, which could also be prepared
by protection of amino alcohol 7b. Reaction of alcohol 12 with
thionyl chloride gave the chloropyrrolidine 13, but this com-
pound proved to be completely inert to substitution reactions
under a range of reaction conditions. Alternatively, reaction of
alcohol 12 with methanesulfonyl chloride gave the correspond-
ing methenesulfonate 14 which did react with o-methoxyphenol
in the presence of potassium tert-butoxide to give pyrrolidine
15. It was expected that the presence of a benzyloxycarbonyl-
MeO
4d R1 = CHMe2, R2 = Me
e R1–R2= CH2CH2CH2
Scheme 3 Reagents: i, NaBH4, H2SO4; ii, H2CO, HCOOH; iii, SOCl2;
iv, o-(MeO)C6H4OH, NaH
valine 6a or (S)-proline 6b with sodium borohydride–conc. sul-
furic acid 15 gave the corresponding amino alcohols 7a,b. N,N-
Dimethylation of 7a and N-methylation of 7b was achieved by
treatment with formaldehyde and formic acid to give N-
methylamino alcohols 8a,b.14 Chlorination of 8a,b with thionyl
chloride gave alkyl chlorides 9a,b, which reacted with o-
methoxyphenol in the presence of sodium hydride to give the
desired ligands 4d,e in overall yields of 19 and 45% from the
commercially available amino alcohols respectively.
The spectral data for catalyst 4d were entirely consistent with
the proposed structure. For amino ether 4e however, the H
1
NMR spectrum showed two singlets at 2.7 and 2.9 ppm corres-
ponding to the N-methyl signal, and in the 13C NMR spectrum
[Fig. 1(b)] twice the expected number of resonances were
observed. These extra peaks could have been due either to the
presence of an impurity in the product, or to compound 4e
existing as two conformers interconverting slowly on the NMR
2892
J. Chem. Soc., Perkin Trans. 1, 1997

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R3
7b
H
vi
R1Li
+
N
R2
80%
16a R2 = R3 = Ph
R
1 = Me, Bu or Ph
i
ii
R
R
2 = PhCH=CH
16b
COOH
CH2OH
CH2Cl
58%
58%
3 = 4-MeOC6H4
N
Z
N
Z
N
Z
12
13
4d,e
iii
Me
O
R2
Me
77%
R1
R2
Ph
NCO
NHR3
Ph
N
N
R1
v
iv
H
O
R3
4e
CH2OMs
90%
40%
N
N
Z
17a–e
18a–e
Z
MeO
17,18 a R1 = Me, R2 = Ph, R3 = Ph
b R1 = Bu, R2 = Ph, R3 = Ph
15
14
Scheme 5 Reagents: i, NaBH4, H2SO4; ii, SOCl2; iii, MsCl, Et3N; iv,
o-(MeO)C6H4OH, KOCMe3; v, LiAlH4; vi, ZONSu (Ms = MeSO2;
Z = PhCH2OCO; Su = succinimide)
c R1 = Me, R2 = PhCH=CH, R3 = 4-MeOC6H4
d R1 = Bu, R2 = PhCH=CH, R3 = 4-MeOC6H4
e R1 = Ph, R2 = PhCH=CH, R3 = 4-MeOC6H4
protecting group on the pyrrolidine nitrogen would prevent the
lone pair of electrons on nitrogen from being involved in this
substitution reaction, and hence prevent the formation of
rearranged products. Finally, reduction of compound 15 with
lithium aluminium hydride again gave catalyst 4e, though in
this case only a single set of peaks were seen in the 1H and 13C
NMR spectra of the catalyst. This synthesis thus proved that
the literature approach to catalysts 4a–d proceeds with
approximately 30% rearrangement to compound 11 when
applied to catalyst 4e. The reason why the relative intensities
and chemical shifts of the 13C NMR signals of a mixture of
compounds 4e and 11 should be temperature dependent is not
clear, but may be due to changes in the relaxation times, or to
the formation of aggregates.
Scheme 6
tions at room temperature), and converted into the correspond-
ing urea by reaction with (S)-1-phenylethyl isocyanate to pro-
vide a reference sample for diastereomeric excess determin-
ations. In each case, the amine was also prepared using ligand
4a,8–10 so that the relative senses of asymmetric induction could
be determined.
From the results given in Table 1, it can be seen that the
presence of compound 11 has no effect upon the catalytic activ-
ity observed with catalyst 4e. Thus comparison of entries 3, 4
and 10 with entries 12, 13 and 14 shows no significant differ-
ences. Interestingly however, the use of catalyst 4e gave the
opposite enantiomer (arising from addition of the organo-
lithium reagent to the si-face of the imine) of amines 17 to that
obtained using catalyst 4a, despite the fact that both catalysts
are derived from an (S)-amino acid. The magnitude of the
enantiomeric excesses are however lower using catalyst 4e than
those reported for catalyst 4a. Ligand 4d however, was found to
preferentially produce the same enantiomer of amines 17 as
ligand 4a, though again with a lower enantiomeric excess.
Asymmetric synthesis of amines
To test the catalytic activity of ligands 4d,e, the addition of
MeLi, BuLi and PhLi to imines 16a,b was investigated as shown
in Scheme 6, the results being presented in Table 1. It was found
necessary to use toluene as a non-coordinating solvent, since in
diethyl ether or THF much lower enantiomeric excesses were
obtained. Under these reaction conditions, no addition of
organolithium reagent to the imine occurred in the absence of
ligands 4d,e. The enantiomeric excess of the amines 17a–e were
determined by reaction with (S)-1-phenylethyl isocyanate to
give ureas 18a–e. The diastereomeric excesses of the ureas could
conveniently be determined by integration of the 1H NMR
spectra, or by HPLC analysis. For each of amines 17a–e, the
corresponding racemic amine was also prepared (from imines
16a,b omitting the chiral ligand 4d,e and conducting the reac-
Conclusions
The synthesis of two new ligands (4d and 4e) for the asym-
metric addition of organolithium reagents to imines has been
achieved. The synthesis of ligand 4e by the standard procedure
reported for similar ligands was found to produce approxi-
mately 30% of compound 11 as an inseparable by-product
obtained due to neighbouring group participation in the final
Table 1 Addition of organolithium reagents to imines induced by ligands 4d,e
Entry
Ligand (%)
R1
R2
R3
Yield (%)
ee (%)
Configuration
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4d (20)
4d (20)
4e (25)
4e (100)
4e (200)
4e (25)
4e (100)
4e (200)
4e (25)
4e (25)
4e (25)
4ed (25)
4ed (100)
4ed (25)
Me
Bu
Me
Me
Me
Bu
Bu
Bu
Ph
Me
Bu
PhCH᎐CH
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
56
33
42
60
42
50
40
37
51
96
44
57
78
78
12
20
10
20
21
12
5.5
1.5
13
10
5.5
9
R
a
᎐
PhCH᎐CH
᎐
PhCH᎐CH
S
S
S
b
b
b
c
S
c
S
S
S
᎐
PhCH᎐CH
᎐
PhCH᎐CH
᎐
PhCH᎐CH
᎐
PhCH᎐CH
᎐
PhCH᎐CH
᎐
PhCH᎐CH
᎐
Ph
Ph
Ph
Me
Me
Me
PhCH᎐CH
4-MeOC6H4
4-MeOC6H4
Ph
᎐
PhCH᎐CH
25
7.5
᎐
Ph
a
Absolute configuration unknown, but shown to be the same as that obtained using catalyst 4a. b Absolute configuration unknown, but shown to be
the opposite to that obtained using catalyst 4a. c Absolute configuration unknown. d Using ligand 4e prepared by the route shown in Scheme 5 and so
not contaminated with compound 11.
J. Chem. Soc., Perkin Trans. 1, 1997
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SN 2 displacement reaction. An alternative synthesis of ligand
4e circumventing this problem has been developed. Both lig-
ands were found to be effective catalysts for the asymmetric
addition of organolithium reagents to imines, and preferentially
produced opposite enantiomers of the resulting amines though
with relatively low enantiomeric excesses. The presence of com-
pound 11 in the reaction mixture was shown to have no effect
upon the catalytic activity of ligand 4e.
At this stage, the reason for the difference in asymmetric
induction observed using ligands 4d and 4e is not clear. Both
catalysts are likely to be tridentate, however it appears that
the conformationally constrained pyrrolidine ring of ligand 4e
occupies different space to the acyclic amino acid sidechains.
This difference in occupied space around the lithium ion may
well be the cause of the reversal of sense of asymmetric induc-
tion, as it may alter the way in which the organolithium
reagent–chiral ligand complex and imine interact. Any more
detailed proposal would be unduly speculative in the absence of
information on the structure of the organolithium–ligand com-
plexes. Our work in this area is continuing, focusing on the
synthesis of new ligands related to compounds 4, but capable of
producing amines with higher enantiomeric excesses. This work
will be reported in due course.
(2S)-1-(o-Methoxyphenoxy)-2-dimethylamino-3-methylbutane
4d
o-Methoxyphenol (16.0 g, 0.13 mol) was added to a suspension
of NaH (3.0 g, 0.125 mol) in DMF (20 ml) at 0 ЊC. The mixture
was stirred at room temperature for 40 min, then a solution
of (2S)-1-chloro-2-dimethylamino-3-methylbutane hydro-
chloride17 9a (4.9 g, 0.033 mol) in DMF (165 ml) was added.
The mixture was stirred at room temperature for 24 h, then
concentrated to approximately 30 ml, diluted with water (80 ml)
and extracted with ether (3 × 80 ml). The combined organic
extracts were washed successively with 10% aq. NaOH, water
and brine, and dried over K2CO3. Concentration in vacuo
afforded catalyst 4d (3.2 g, 41%) as a slightly pink oil, [α]D20 ϩ2.8
(c 1.0, EtOH); νmax(film)/cmϪ1 3150w, 2957s, 1677s and 1594m;
δH 0.90 (3H, d, J 6.7, CH3), 1.00 (3H, d, J 6.7, CH3), 2.03 (1H,
octet, J 6.7, Me2CH), 2.37 (6H, s, NMe2), 2.45–2.55 (1H, m,
NCH), 3.79 (3H, s, OCH3), 4.12 (2H, d, J 4.6, OCH2) and 6.85–
6.95 (4H, m, Ph); δC 19.78 (q), 21.00 (q), 28.19 (d), 42.05 (q),
56.06 (d), 66.50 (t), 68.87 (q), 112.23, 113.49, 120.86 and 121.07
(d), 148.57 and 149.81 (s); m/z (EI) 237 (Mϩ, 14%) and 194
(100) (Found: Mϩ, 237.1729. C14H23NO2 requires M, 237.1729).
(2S)-N-Methyl-2-(o-methoxyphenoxymethyl)pyrrolidine 4e,
route A
The above method was followed using: sodium hydride (12.0 g
of 60% dispersion in oil, 0.30 mol), DMF (440 ml),
2-methoxyphenol (32 ml, 36.1 g, 0.30 mol) and (2S)-N-methyl-
2-chloromethylpyrrolidine hydrochloride17 9b (11.84 g, 0.070
mol). The product was distilled under reduced pressure (0.5
mmHg, 130 ЊC) to give compound 4e as a clear oil (13.4 g,
87%). Analytical data are given in route B.
Experimental
1H NMR spectra were recorded at 250 MHz on a Brucker
1
AM250 spectrometer fitted with a H–13C dual probe, and were
recorded at 293 K in CDCl3 unless otherwise stated. Spectra
were internally referenced either to TMS or to the residual solv-
ent peak, and peaks are reported in ppm downfield of TMS.
Multiplicities are reported as singlet (s), doublet (d), triplet (t),
quartet (q), some combination of these, broad (br) or multiplet
(m). J Values are given in Hz. 13C NMR spectra were recorded
at 62.5 MHz on the same spectrometer as 1H NMR spectra, at
293 K and in CDCl3 unless otherwise stated. Spectra were refer-
enced to the solvent peak, and are reported in ppm downfield
of TMS. Peak assignments were made by DEPT editing of the
spectra. Infrared spectra were recorded on a Perkin Elmer 1600
series FTIR spectrometer, only characteristic absorptions are
reported, and peaks are reported as strong (s), moderate (m),
weak (w) or broad (br). Mass spectra were recorded using the
FAB technique (Csϩ ion bombardment at 25 kV) on a VG Auto-
spec spectrometer, or by chemical ionisation (CI) with ammo-
nia on either a VG model 12-253 quadrupole spectrometer or a
VG Quattro II triple quadrupole spectrometer. Only significant
fragment ions are reported, and only molecular ions are
assigned. High resolution mass measurements were made on a
VG ZAB-E spectrometer. Optical rotations ([α]D ) were recorded
on an Optical Activity Ltd. Polar 2001 polarimeter, and are
reported in units of 10Ϫ1 deg cm2 gϪ1 along with the solvent and
concentration in g per 100 ml. Melting points are uncorrected.
Elemental analyses were performed within the Chemistry
department on a Carolo Erba Model 1106 or Model 1108
analyser.
(2S)-N-Benzyloxycarbonyl-2-methylsulfonyloxypyrrolidine 14
Methanesulfonyl chloride (0.37 g, 0.25 ml, 3.2 mmol) was
added to
a stirred solution of (S)-N-benzyloxycarbonyl-
prolinol15 12 (0.5 g, 2.1 mmol) and triethylamine (0.32 g, 3.2
mmol) in CH2Cl2 (50 ml), and the solution stirred overnight.
The reaction was washed with 2  aq. HCl (40 ml), 5% aq.
K2CO3 (40 ml) and water (40 ml), then the organic phase was
dried over MgSO4 before filtering and evaporating solvent in
vacuo. A brown oil was obtained which was purified by flash
chromatography (hexane–EtOAc, 1:1). The desired product 14
(0.51 g, 77%) was obtained as a clear oil, [α]D26 Ϫ54.4 (c 1.7,
CHCl3); νmax(film)/cmϪ1 3030w, 2959m, 1734m, 1701s, 1413s,
1357s and 1175s; δH 1.9–2.1 [4H, m, (CH2)2], 2.8 and 2.9 (3H,
2 × s, CH3SO2), 3.4–3.5 (2H, m, CH2N), 4.1–4.4 (3H, m,
CH2O ϩ NCH), 5.2 (2H, s, CH2Ph) and 7.3–7.4 (5H, m, C6H5);
δC 22.9 and 23.7 (t), 27.7 and 28.5 (t), 36.8 (q), 46.8 and 47.1 (t),
55.6 and 56.3 (d), 66.8 and 67.1 (t), 69.3 and 69.5 (t), 127.8,
128.0, 128.2 and 128.5 (d), 136.4 and 136.7 (s) and 154.9 (s); the
multiple peaks in the 1H and 13C NMR spectra were due to the
presence of rotamers about the urethane amide bond; m/z (CI,
NH3) 314 (MHϩ, 25%), 218 (45), 145 (85) and 84 (100) (Found:
MHϩ, 314.1062. C14H20NO5S requires M, 314.1062).
Analytical HPLC was carried out on a Waters HPLC system
using a Regis R,R WHELKO-1 chiral stationary phase and
detection by UV absorption at 254 nm. A solvent system of
isopropyl alcohol (IPA)–hexane at a flow rate of 2.0 ml minϪ1
was used. Flash chromatography16 was carried out on 40–60
µm mesh silica, thin layer chromatography was carried out on
aluminium backed silica plates (0.25 mm depth of silica con-
taining UV254), and the plates were visualised with UV light,
and/or dodecaphosphomolybdic acid as appropriate.
All yields refer to isolated, purified material, and are unopti-
mised. THF and diethyl ether were dried by distillation from
sodium immediately prior to use. Toluene was dried over
sodium wire. Other solvents were used as supplied. Ether refers
to diethyl ether. Petrol refers to the fraction of light petroleum
with bp 40–60 ЊC.
(2S)-N-Benzyloxycarbonyl-2-(o-methoxyphenoxymethyl)-
pyrrolidine 15
To a solution of potassium tert-butoxide (4.10 g, 36.5 mmol) in
dry tert-butyl alcohol (40 ml) was added a solution of 2-
methoxyphenol (4.53 g, 36.5 mmol) in tert-butyl alcohol (40 ml)
followed by
a
solution of (2S)-N-benzyloxycarbonyl-2-
methylsulfonyloxypyrrolidine 14 (2.86 g, 9.12 mmol) in tert-
butyl alcohol (40 ml). The reaction was heated to reflux over-
night before concentration in vacuo and dilution with EtOAc
(100 ml). The solution was washed with 2  aq. HCl (100 ml),
water (100 ml) and brine (100 ml), and then dried over MgSO4,
filtered and concentrated in vacuo to give an orange oil. This
was purified by flash chromatography (hexane–EtOAc, 4:1) to
give compound 15 (2.22 g, 71%) as a colourless oil, [α]D20 Ϫ40.0 (c
1.0, CHCl3); νmax(film)/cmϪ1 3063m, 2953s, 1697s, 1505s, 1454s,
2894
J. Chem. Soc., Perkin Trans. 1, 1997

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1410s and 1253s; δH 1.8–2.1 [4H, m, (CH2)2], 3.3–3.5 (2H, m,
CH2N), 3.8 (3H, s, OCH3), 4.0–4.1 (1H, m, CH), 4.1–4.2 (2H,
m, CH2O), 5.1 (2H, s, CH2Ph), 6.8–6.9 (4H, m, C6H4OCH3)
and 7.2–7.3 (5H, m, C6H5); δC 22.7 and 23.7 (t), 28.0 and 28.7
(t), 46.7 and 47.1 (t), 56.0 (q), 55.7 and 56.4 (d), 66.7 and 67.1
(t), 68.5 and 69.0 (t), 113.4, 113.5, 120.1, 127.8, 128.1 and 128.5
(d), 136.6, 136.9, 148.1 and 148.5 (s), 154.9 and 155.1 (s); m/z
(CI, NH3) 342 (MHϩ, 90%), 208 (70), 84 (100) (Found: Mϩ,
342.1705. C20H24NO4 requires M, 342.1705).
procedure, δH 1.3 (3H, d, J 6.9, CH3), 1.4 (3H, d, J 7.2, CH3),
4.2 (1H, d, J 7.4, NH), 5.1 (1H, q, J 7.0, CHCH3), 6.1 (1H,
2 × q, 7.1, CHCH3), 6.8 (2H, m, NC6H5) and 7.1–7.4 (13H, m,
C6H5); enantiomeric excess 12%; chiral HPLC, hexane–IPA,
3:2, 3.03 min (17%), 4.05 min (22%), 12.8% ee; absolute con-
figuration (S).
1-Phenylamino-1-phenylpentane 17b10
The general procedure was followed using ligand 4e, and the
product was purified by flash chromatography (petrol–Et2O,
20:1) to give amine 17b in 44% yield, [α]D23 ϩ0.90 (c 1.0, CHCl3);
νmax(film)/cmϪ1 3412m, 3051m, 2954s, 1600s, 1502s and 1317s;
δH 0.75 (3H, t, J 7.0, CH3), 1.0–1.3 [4H, m, (CH2)2], 1.5–1.7 (2H,
m, CH2), 3.8–4.0 (1H, br s, NH), 4.15 (1H, t, J 6.8, CH), 6.4
(2H, d, J 7.6, NC6H5), 6.5 (1H, t, J 7.3, NC6H5), 7.0 (2H, t, J
7.9, NC6H5) and 7.1–7.3 (5H, m, C6H5). The corresponding
urea 18b was prepared following the general procedure and ana-
lysed by chiral HPLC, hexane–IPA, 9:1, 5.64 min (46%), 6.43
min (41%), 5.7% ee.
(2S)-N-Methyl-2-(o-methoxyphenoxymethyl)pyrrolidine 4e,
route B
LiAlH4 (0.02 g, 0.52 mmol) was added to a stirring solution of
compound 15 (52 mg, 0.15 mmol) in dry THF (10 ml) at 0 ЊC
and the mixture was heated under reflux for 2 h. The reaction
was cooled to room temperature and diluted with EtOAc (2 ml)
followed by water (20 ml), acidified to pH 3 using 2  aq. HCl,
and washed with ether (2 × 20 ml). The aqueous layer was bas-
ified (pH 10) using 2  aq. NaOH and extracted with EtOAc
(2 × 20 ml), the EtOAc extracts were combined and dried over
MgSO4 prior to filtering and removing solvent in vacuo. Com-
pound 4e (30 mg, 90%) was obtained as a colourless oil, [α]D26
Ϫ38.4 (c 1.1, CHCl3); νmax(film)/cmϪ1 2938s, 2779s, 1592s and
1505s; δH 1.7–1.9 [3H, m, (CH2)2], 2.1–2.2 [1H, m, (CH2)2],
2.4–2.5 (1H, m, CH2N), 2.6 (3H, s, CH3N), 3.0 (1H, pseudo
quintet, J 6.6, NCH), 3.3–3.4 (1H, m, CH2N), 3.9 (3H, s,
CH3O), 4.0 (1H, dd, J 5.6, 9.8, CH2O), 4.2 (1H, dd, J 5.7, 9.7,
CH2O) and 6.9–6.95 (4H, m, C6H4OCH3); δC 22.6 (t), 28.6 (t),
41.1 (q), 55.9 (q), 57.2 (t), 64.5 (d), 71.1 (t), 112.0, 113.8, 120.9
and 121.5 (d), 148.3 and 149.6 (s); m/z (EI) 221 (Mϩ, 3%) and
84 (100) [Found: (CI, NH3) MHϩ, 222.1494. C13H20NO2
requires M, 222.1495].
3-[(p-Methoxyphenyl)amino]-1-phenylbut-1-ene 17c10
The general procedure was followed using ligand 4d or 4e, and
the product was purified by flash chromatography (petrol–Et2O,
5:1), giving amine 17c as a yellow oil in 42% yield, [α]D25 Ϫ29.5 (c
1.0, CHCl3) using ligand 4e; [α]D20 ϩ20.5 (c 2.6, CHCl3) using
ligand 4d; νmax(film)/cmϪ1 3394m, 3055m, 2964s, 1616m, 1511s
and 1448s; δH 1.45 (3H, d, J 6.6, CH3), 3.2–3.6 (1H, br s, NH),
3.8 (3H, s, OCH3), 4.1 (1H, quintet, J 6.2, CH), 6.25 (1H, dd, J
5.9, 15.9, CH᎐CHPh), 6.6 (1H, d, J 15.5, CH᎐CHPh), 6.65 (2H,
᎐
᎐
d, J 8.9, C6H4OCH3), 6.8 (2H, d, J 8.9, C6H4OCH3) and 7.2–7.4
(5H, m, C6H5). The corresponding urea 18c was prepared fol-
lowing the general procedure, δH 1.2 (3H, 2 × d, J 6.9, CH3),
1.35 (3H, 2 × d, J 6.9, CH3), 3.85 (3H, s, OCH3), 4.25 (1H, d,
J 7.8, NH), 5.0 (1H, m, CHCH3), 5.5 (1H, quintet, J 6.7,
General procedure for the asymmetric alkylation of imines using
organolithium reagents
CHCH᎐CH), 6.2 (1H, dd, J 6.5, 15.9, CH᎐CHPh), 6.5 (1H, d, J
᎐
᎐
A solution of the appropriate organolithium reagent (BuLi,
MeLi or PhLi) (3.0 mmol) was added to a stirred solution of
imine 16a,b (2.0 mmol) and chiral ligand 4d,e (0.5 to 4.0 mmol)
in toluene (70 ml) at Ϫ78 ЊC under a nitrogen atmosphere. The
solution was stirred at this temperature for 3 h and sub-
sequently at Ϫ50 ЊC for 3 h, before quenching with water (20
ml). The reaction mixture was washed with 5% aq. K2CO3 and
the aqueous layer back extracted with EtOAc. The combined
organic extracts were again washed with water and brine before
being dried over K2CO3 and evaporated in vacuo to leave an
orange residue which was purified by flash chromatography to
give amines 17a–e.
15.9, CH᎐CHPh), 6.9 (2H, d, J 8.8, C H OCH ), 7.1 (2H, d,
᎐
6
4
3
J 8.8, C6H4OCH3) and 7.15–7.4 (10H, m, C6H5). Enantiomeric
excess 12% in favour of the (R)-enantiomer using ligand 4d and
19% in favour of the (S)-enantiomer using ligand 4e. Chiral
HPLC, hexane–IPA, 1:1, 4.33 min (58%), 13.45 min (35%),
25% ee using ligand 4e.
3-[(p-Methoxyphenyl)-1-phenylhept-1-ene 17d10
The general procedure was followed using ligand 4d or 4e, and
the product was purified by flash chromatography (petrol–Et2O,
6:1) to give amine 17d in 40% yield, [α]D24 Ϫ1.8 (c 1.0, CHCl3)
using ligand 4e, [α]D20 7.2 (c 1.0, CHCl3) using ligand 4d;
νmax(film)/cmϪ1 3398m, 3056s, 2928s, 1617m, 1517s and 1463s;
δH 0.95 (3H, t, J 6.8, CH3), 1.3–1.6 [4H, m, (CH2)2], 1.6–1.8 (2H,
m, CH2), 3.3–3.4 (1H, br, NH), 3.75 (3H, s, OCH3), 3.9 (1H, q, J
General procedure for the preparation of ureas 18a–e
To a solution of amine 17a–e (20–50 mg) in CDCl3 (0.5 ml) was
added (S)-1-phenylethyl isocyanate (15 µl, 18 mg, 0.23 mmol).
The resulting solution was allowed to stand at room tempera-
ture for 24 h to enable the reaction to reach completion, before
6.5, NCH), 6.15 (1H, dd, J 6.5, 15.9, CH᎐CHPh), 6.55 (1H, d,
᎐
J 15.9, PhCH᎐CH), 6.6 (2H, d, J 9.0, C H OCH ), 6.8 (2H, d, J
᎐
6
4
3
1
8.9, C6H4OCH3) and 7.2–7.5 (5H, m, C6H5). The corresponding
urea 18d was prepared following the general procedure, and
analysed by chiral HPLC, hexane–IPA, 2:3, 4.09 min (49%),
6.22 min (44%), 5.4% ee. Absolute configuration was not
assigned, however the configuration using ligand 4e is the
opposite to that obtained using catalyst 4a.
analysis of ureas 18a–e by H NMR spectroscopy and HPLC
1
without purification. If unreacted amine was detected by H
NMR, then a further batch of isocyanate was added and the
solution again allowed to stand for 24 h before analysis. No
evidence of any kinetic resolution was observed during this
derivatisation, and all of the amine 17a–e was consumed (as
1
judged by H NMR) before any analysis of the enantiomeric
3-[(p-Methoxyphenyl)amino]-1,3diphenylprop-1-ene 17e10
The general procedure was followed, and the product was puri-
fied by flash chromatography (petrol–EtOAc, 6:1) to yield
amine 17e in 51% yield, [α]D18 Ϫ3.7 (c 1.0, CHCl3); νmax(CH2Cl2)/
cmϪ1 3399m, 3025s, 2830s, 1598s and 1510m; δH 3.75 (3H, s,
OCH3), 3.8–4.0 (1H, br s, NH), 5.05 (1H, d, J 6.3, NCH), 6.4
(1H, dd, J 6.2, 15.8, CH᎐CHPh), 6.6 (3H, m, CH᎐CHPh,
excess was undertaken.
1-Phenylamino-1-phenylethane 17a 18
The general procedure was followed using ligand 4e, and the
product was purified by flash chromatography (petrol–Et2O,
5:1) to give amine 17a in 96% yield, [α]D24 ϩ0.80 (c 1.0, EtOH);
νmax(film)/cmϪ1 3409m, 3082m, 2968s, 1600s, 1505s and 1318s;
δH 1.5 (3H, d, 6.7, CH3), 4.0–4.2 (1H, br s, NH), 4.5 (1H, q,
J 6.7, CHCH3), 6.5 (2H, d, J 7.6, NC6H5), 6.6 (1H, t, J 7.3,
NC6H5), 7.1 (2H, t, J 7.9, NC6H5) and 7.2–7.5 (5H, m, C6H5).
The corresponding urea 18a was prepared following the general
᎐
᎐
C6H4OCH3), 6.85 (2H, d, J 8.9, C6H4OCH3) and 7.2–7.5 (10H,
m, C6H5). The corresponding urea 18e was prepared following
the general procedure, δH 1.3 (3H, d, J 6.9, CH3), 3.8 (3H, s,
OCH3), 4.4 (1H, d, J 7.8, NH), 5.1 (1H, quintet, J 7.5,
J. Chem. Soc., Perkin Trans. 1, 1997
2895

View Article Online
L. Cipolla, L. Lay, F. Nicotra, C. Pangrazio and L. Panza,
Tetrahedron, 1995, 51, 4679; T. Basile, A. Bocoum, D. Savoia and
A. Umanironchi, J. Org. Chem., 1994, 59, 7766.
5 M. S. Iyer, K. M. Gigstad, N. D. Namdev and M. Lipton, J. Am.
Chem. Soc., 1996, 118, 4910.
6 S. E. Denmark, N. Nakajima and O. J.-C. Nicaise, J. Am. Chem.
Soc., 1994, 116, 8797.
CHCH ), 6.3 (1H, dd, J 8.5, 15.7, CH᎐CHPh), 6.5 (1H, d, J
᎐
3
8.6, CH), 6.7 (1H, d, J 15.9, CH᎐CHPh), 6.8–7.0 (4H, m,
᎐
C6H4OCH3) and 7.2–7.5 (15H, m, C6H5); enantiomeric excess
11%; chiral HPLC, hexane–IPA, 3:2, 6.52 min (45%), 10.32
min (35%), 12.5% ee.
7 S. Itsuno, M. Sasaki, S. Kuroda and K. Ito, Tetrahedron:
Asymmetry, 1995, 6, 1507.
Acknowledgements
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50, 4429.
9 I. Inoue, M. Shindo, K. Koga, M. Kanai and K. Tomioka,
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13 A preliminary account of some of this work has been reported:
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1995, 36, 7885.
14 M. Kitamoto, K. Kameo, S. Terashima and S-I. Yamada, Chem.
Pharm Bull., 1977, 25, 1273; K. Tomioka, Y. Shinmi, K. Shiina,
M. Nakajima and K. Koga, Chem. Pharm. Bull., 1990, 38, 2133.
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The authors thank the EPSRC and Smithkline Beechams for a
CASE award studentship to C. A. J., and the EU for a student-
ship to M. M. Mass spectra were recorded by the staff of the
EPSRC service at the University of Wales, Swansea.
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Paper 7/02028G
Received 24th March 1997
Accepted 11th June 1997
2896
J. Chem. Soc., Perkin Trans. 1, 1997