Enantioselective addition of methyllithium to aromatic imines catalyzed by C2 symmetric tertiary diamines

Article abstract of DOI:10.1016/j.tet.2005.07.008

Enantioselective addition of methyllithium to aromatic imines catalyzed by C₂ symmetric tertiary diamines is described. Eleven diamines have been tested, for which dramatic effect of the nitrogen substitution has been observed. Diamines bearing hindered group close to the nitrogen led to racemic product while homologous hindered diamines led to the best results. Enantiomeric excess up to 74% could be achieved. An explanation of the absolute configuration of the product obtained is given considering the mechanism of the reaction.

Full text of DOI:10.1016/j.tet.2005.07.008

Tetrahedron 61 (2005) 8939–8946
Enantioselective addition of methyllithium to aromatic imines
catalyzed by C2 symmetric tertiary diamines
Jean-Claude Kizirian,a Noemi Cabello,a Laurent Pinchard,b Jean-Claude Cailleb
and Alexandre Alexakisa,
*
aDepartment of Organic Chemistry, University of Geneva, 30, Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
bPPG-SIPSY, Z. I. La croix cadeau, B.P. 79, 49242 AVRILLE Cedex, France
Received 30 May 2005; revised 5 July 2005; accepted 5 July 2005
Available online 26 July 2005
Abstract—Enantioselective addition of methyllithium to aromatic imines catalyzed by C2 symmetric tertiary diamines is described.
Eleven diamines have been tested, for which dramatic effect of the nitrogen substitution has been observed. Diamines bearing
hindered group close to the nitrogen led to racemic product while homologous hindered diamines led to the best results.
Enantiomeric excess up to 74% could be achieved. An explanation of the absolute configuration of the product obtained is given
considering the mechanism of the reaction.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
enantioselective addition of methyllithium to aromatic
imines, dramatic variations in selectivities have been
observed depending on R substituent. On the contrary,
in the case of diamine 1a, both nitrogen atoms bearing
four identical substituents cannot become stereogenic
centers.4 We would like to disclose in this article the
complete study concerning the enantioselective addition
of methyllithium to aromatic imines catalyzed by our
diamines. Furthermore, mechanistic considerations will
be discussed to explain the stereochemical outcome of
the reaction.
The discovery of new ligands for enantioselective reactions
is one of the major goals in asymmetric synthesis. Diamines
have often been used as chiral inducers and have turned out
to be a powerful tool in inducing high levels of
enantioselectivity.1 Their ability to be associated with
several metals makes them even more attractive as a wide
range of reactions can be performed in the presence of
diamines.2 We are interested in the continuing development
of these ligands by modifying their structures and
substituents to improve their selectivities and extend their
application.3 In that context, we recently reported concep-
tually new chiral tertiary diamines 1 capable to generate,
when associated with organolithium reagents, reactive
intermediates 2, which contain a chiral nitrogen atom.4 In
the five membered ring formed with a metallic species, the
more bulky nitrogen substituent adopts a trans relationship
with the R2 group of the carbon backbone (Scheme 1).
Similar conceptually chiral diether ligands have been
studied, for which stereogenic oxygen atoms are involved
in the reactive intermediate.5 Many ligands including
(K)-sparteine have been used for the enantioselective
addition of organometallic reagents to imines.6
In our preliminary study, concerning the catalytic
Keywords: Asymmetry; Diamines; Organolithium; Imines; Catalysis.
*
Corresponding author. Tel.: C41 22 379 65 22; fax: C41 22 379 32 15;
e-mail: alexandre.alexakis@chiorg.unige.ch
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.008

8940
J.-C. Kizirian et al. / Tetrahedron 61 (2005) 8939–8946
prepared very easily on a large scale following the two steps
procedure previously described.8 Concerning the synthesis
of bulkier ligand 1k, reductive amination failed: only traces
of the product were detected even after several days of
reaction. Therefore, a three-step procedure was followed:
bis-amide 6 was easily prepared from 4 and reduced with
LAH to give the corresponding secondary diamine in
moderate yield after 2 weeks. Finally, an Eschweiler–Clark
methylation led to the desired ligand 1k (Scheme 4,
Table 1).
Scheme 2.
2. Synthesis of diamine ligands
Diamines 1a–j have all been prepared in good yields from
the same starting material 4 readily available on a large
scale.7 Ligand 1a was obtained by an Eschweiler–Clark
reaction directly performed on 4 (Scheme 2) while ligands
1b–j have been obtained by reductive amination of
N,N0-dimethyl-1,2-cyclohexanediamine 5 with the appro-
priate aldehyde (Scheme 3, Table 1). Diamine 5 can be
3. Results and discussion
In a preliminary study, the efficiency of diamines were
evaluated in the addition of methyllithium to imine 7. We
compared first diamines 1a and 1g under stoichiometric
conditions and found that the adduct was formed in 20 and
48% ee, respectively, which validates our starting
hypothesis.
As methyllithium was reacting very slowly with imines at
K78 8C without activation (6% yield after 120 min at
K78 8C),9 catalysis was thought to be possible and indeed
we observed that 0.2 equiv of diamine was sufficient to
maintain good yields without any loss of enantioselectivity.
Therefore, all of the other diamines were tested in catalytic
amount. A strong influence of the lateral chain was
observed. By changing R from H to ethyl and n-propyl led
to an increase of the ee. When bulkier substituents with
ramified alkyl chains were placed close to the nitrogen
atom, the products were obtained as a racemic mixture in
good yields (Table 2, entries 4, 11, and 12). On the contrary,
when the size of the bulky substituent increased in the b
position to the nitrogen atom, an increase in ee was observed
again. Indeed, the best selectivity was obtained with diamines
1f and 1h (Table 2, entries 6 and 9). Moving the bulky
substituent another methylene unit away did not improve the
selectivity but the corresponding ligand 1i was still efficient
as the product was obtained in 58% ee (Scheme 5).
Scheme 3.
Scheme 5.
Scheme 4.
Table 2. Enantioselective addition of MeLi to imine 7 with diamines 1a–k
Table 1. Reductive amination of N,N0-dimethyl-1,2-cyclohexanediamine
producing ligands 1b–j
Entry
Ligand
Equivalent
Yield%
ee%
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1g
1h
1i
2
78
93
93
94
94
98
78
94
98
93
95
76
20 (R)
24 (R)
34 (R)
0
53 (R)
67 (R)
48 (R)
40 (R)
68 (R)
58 (R)
0
0.2
0.2
0.2
0.2
0.2
0.2
2
0.2
0.2
0.2
0.2
Entry
Product
R
Yield%
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
1g
1h
1i
Et
n-Pr
68
89
72
82
83
49
82
75
87
iPr
iBu
CHt2Bu
Ph
9
CH2Ph
CH2CH2Ph
2,4,6-Me3–C6H2
10
11
12
1j
1k
1j
0

J.-C. Kizirian et al. / Tetrahedron 61 (2005) 8939–8946
8941
Table 4. Enantioselective addition of MeLi to imines 7 and 13a–h with
diamines 1f and 1h
Entry
Substrate
Ligand
Yield%
ee%a
1
7
1h
1h
1f
1h
1f
1h
1f
1f
1f
1f
1h
1h
98
50
70
57
70
35
94
93
87
78
42
88
68 (R)
74
2
13a
13b
13b
13c
13c
13d
13e
13f
13g
13g
13h
3b
4
57 (C)
68 (C)
38 (K)
58 (K)
20
58
4
42
5
6
7
8
Scheme 6.
We have evaluated the efficiency of our best diamines on
other imines. Initially, the para-methoxy phenyl moiety was
selected because it is an easily removable protecting group
of the nitrogen functionality. However, it appears to be more
difficult in some cases.9–11 Nevertheless, we have checked
the influence of an ortho substituent such as in substrates 9
and 10 (Table 3). The ortho-methoxy substituent was found
to accelerate considerably the rate of the addition, thus,
allowing a fast addition of methyllithium through the non
catalyzed process. Therefore, the selectivity obtained with
diamine 1f on imine 9 was very low. Imine 10 has improved
the selectivity of the addition compared to the non ortho-
substituted imines only when diamine 1a was used (Table 3,
entry 3). On the contrary, while 1f led to 67% ee with 7, the
selectivity dropped to 20% ee with the ortho isopropyl
substituted imine 10 (Table 3). This result is in sharp
contrast with the result obtained with ligand 1a and with the
result reported by Tomioka.9,10 We can explain these
differences by the great sensitivity of our diamines to steric
hindrance. However, this behavior had already been
observed with (K)-sparteine12 and when the fine tuning of
our diamines 1a–1k were made (Table 2). In the case of
substrates as well, when steric hindrance was increased
close to the reaction site, unfavored steric interactions
appear with the hindered diamine 1f (Scheme 6).
9
10c
11c
12
68
48 (C)
(a) Absolute configuration or sign of the optical rotation. (b) Reaction run at
K65 8C. (c) Reaction run at K30 8C.
phenyl derivatives 13a–c showing quite small electronic
effects. On the other hand, the reactivity was found to be
very different in some cases: for instance, poor yields were
obtained with imines 13g and 13h, which reacted at K65
and K30 8C, respectively. Heteroaromatic substituted
imines 13d–f showed as well a very different behavior.
Unlike imine 13e, with the thienyl substitution, both imines
13d and 13f were not good substrates (Scheme 7).
This difference can be explained by the availability of the
lone pair of the heteroatom in the aromatic ring system. As
this lone pair is less engaged in the aromaticity of the
heteroaromatic ring for pyridyl and furyl compared to
thienyl, the corresponding imines 13d and 13f are much
more activated than 13e and react easily in a non-catalyzed
process leading to the products with low selectivities.
The absolute configuration of product 8 has been already
reported by Tomioka et al.9 By using Tomioka’s ligand, we
have been able to assign by comparison the R absolute
configuration for amine 8 when we have used our diamines.
If the same stereochemical pathway is assumed for all
imines employed, compounds 14a–h should present the
same R configuration as for product 8. To explain these
results, we think that a first complexation occurs between
the diamine–MeLi complex and the nitrogen lone pair of the
imine leading to the intermediate 15 close to the transition
state (Scheme 8). The latter is reached after a small rotation
of the imine double bond. If the imine turns to react with its
Si face (ET1, Scheme 8), an unfavorable interaction appears
between the PMP nitrogen substituent and the R part of the
ligand. On the contrary, if the imine turns to react with its Re
face (ET2, Scheme 8), a much more favored transition state
is formed without destabilizing interactions. The addition
occurs on the Re face of the imine leading to the product of
R configuration.
Table 3. Enantioselective addition of MeLi to imine 9–10 with diamines 1a
and 1f
Entry
Substrate
Ligand
Yield%
ee%
1
2
3
4
9
9
10
10
1a
1f
1a
1f
82
77
99
93
6
2
24
20
The aldehyde part of the imines were changed with other
aromatic substitution. Imines 13a–h were tested under the
same experimental conditions as 7 with diamines 1h or 1f.
Although, both diamines 1f and 1h gave the same selectivity
for imine 7, diamine 1h was usually found to be superior
to 1f with imines 13a–h (Table 4). Similar levels of
enantioselectivity were obtained with para substituted
It has been noticed that increasing the amount of
methyllithium accelerates the rate of the reaction. One
reason for that has already been discussed by Tomioka et
al.9 by considering that the amide product can also be a
ligand for the diamine. We envisioned a 6 centers transition
state, in which two methyllithium aggregates to reach the
most favored transition state ET2 (Scheme 8). It then
follows that with 1 equiv of methyllithium, much lower
yields are obtained and it is very difficult for the reaction to
Scheme 7.

8942
J.-C. Kizirian et al. / Tetrahedron 61 (2005) 8939–8946
Scheme 8.
go to completion. In the catalytic process, we used only 20%
of diamine with respect to substrate and 3 equiv of
methyllithium, meaning that the ratio diamine–RLi is
actually close to 7%. In that situation, and in a non polar
solvent such as toluene, it can be reasonable to consider the
methyllithium in a more aggregated state than the dimeric
reactive intermediate. The second lithium of this species is
likely complexed by diethylether present in the reaction
medium (methyllithium is available as solution in diethy-
lether). The theoretical studies dedicated to the aldehyde/
alkyllithium condensation problem are relatively scarce13
while no description of the addition pathway of organo-
lithium reagents onto imines has been reported to our
knowledge. Nevertheless, in the case of aldehydes, the
formation of an open dimer intermediate, which converts
into a six membered cyclic transition state has been
preferred by theoretical studies.13
hindered diamines with bulky substituents a to the nitrogen
atom, the adduct was formed without any selectivity. As the
chiral discrimination should have been much stronger with
these diamines (1d, 1j, 1k), it seems reasonable to envision,
for the diamine/RLi complex, the existence of the
equilibrium of complexes 15 and 16 through the free
diamine (Scheme 9). When R becomes too bulky, a
competitive unfavored interaction between CH2R and Me
of methyllithium could lead to complex 16, which is close to
a meso situation. The reactive complex 17 would lead to a
non selective process as little spatial discimination exists.
Further studies are under progress to obtain spectroscopic
evidence about the real reactive species with the aim of
establishing a more accurate mechanism.
In conclusion, new ligands have been developed for the
catalytic asymmetric addition of methyllithium to imines.
We have demonstrated that in this new ligand family, the
asymmetric induction can be enhanced by a stereogenic
nitrogen atom. These new diamines are of interest because
they are easy to prepare on a large scale in enantiomerically
pure form, stable on storage and recoverable after use.
By choosing the appropriate nitrogen substituents, enantio-
selectivities up to 74% have been obtained. A model, which
could explain the stereochemical outcome of the reaction
has been proposed. Further studies are currently in progress
in our laboratory to give experimental support to this
mechanism and to find more efficient and more general
diamines.
For less hindered diamines such as 1b, 1c, 1e or 1h, ET1 can
explain in part the lower selectivities obtained. But for
4. Experimental
4.1. General
Unless otherwise stated, all reagents were employed as
received. Solvent were distilled on CaH2 or Na/benzo-
phenon. NMR spectrum were made on BRUCKER
Scheme 9.

J.-C. Kizirian et al. / Tetrahedron 61 (2005) 8939–8946
8943
400 MHz for proton and BRUCKER 100 MHz for carbon in
CDCl3.
MS (m/z) 254, 239, 211, 197, 166, 139, 126, 100, 84, 57.
HRMS calcd for C16H34N2 254.2722, found 254.2719.
4.1.1. N,N,N0N0-(1R,2R)-Tetramethylcyclohexane-1,2-
diamine 1a. (R,R)-1,2-Diammoniumcyclohexane mono-
(C)-tartrate salt 5 (24 g, 0.091 mol) was dissolved in
formic acid 85% (36 mL) and formaldehyde 40% (44 mL)
was added slowly at room temperature. The mixture was
heated at reflux 2 h. After cooling, the reaction mixture was
made basic until pH 14 and extracted with ether. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The product was distilled (bpZ50 8C/0.1 mmHg) to give a
colorless liquid (11.35 g, 74%). 1H NMR: d(ppm) 1.05–1.15
(m, 4H), 1.68–1.74 (m, 2H), 1.78–1.90 (m, 2H), 2.26 (s,
12H), 2.35–2.40 (m, 2H). 13C NMR: d(ppm) 22.8, 25.6,
40.1, 63.8. [a]2D0Z K62.9 (c 1.05, CHCl3).
4.2.4. (1R,2R)-N,N0-Bis-(3-methylbutyl)-N,N0-dimethyl-
cyclohexane-1,2-diamine 1e. The product was obtained
according to the general procedure and purified by
distillation (bpZ130–140 8C/1 mmHg) and isolated as a
1
colorless oil in 82% yield. H NMR: d(ppm) 0.87 (d, JZ
2.0 Hz, 6H), 0.89 (d, JZ2.0 Hz, 6H), 1.03–1.22 (m, 4H),
1.26–1.40 (m, 4H), 1.57 (s, JZ6.6 Hz, 2H), 1.65–1.72 (m,
2H), 1.74–1.82 (m, 2H), 2.23 (s, 6H), 2.42–2.56 (m, 6H).
13C NMR: d(ppm) 22.8, 23.0, 25.5, 25.9, 26.5, 36.7, 37.6,
52.6, 62.9. [a]2D0Z K27.2 (c 1.02, CHCl3). MS (m/z) 282,
267, 239, 211, 197, 180, 140, 126, 114, 84, 58. HRMS calcd
for C18H38N2 282.3035, found 282.3026.
4.2.5.
(1R,2R)-N,N0-Bis-(3,3-dimethyl-butyl)-N,N0-
dimethyl-cyclohexane-1,2-diamine 1f. The product was
obtained according to the general procedure, purified by
distillation (bpZ150 8C/1 mmHg) and isolated as a color-
less oil in 83% yield. 1H NMR: d(ppm) 0.90 (s, 18H), 1.05–
1.25 (m, 4H), 1.35–1.45 (m, 4H), 1.67–1.74 (m, 2H), 1.76–
1.83 (m, 2H), 2.25 (s, 6H), 2.42–2.58 (m, 6H). 13C NMR:
d(ppm) 22.3, 25.9, 29.6, 29.8, 37.0, 42.2, 50.1, 62.7. [a]2D0Z
K31.1 (c 1.02, CHCl3). MS (m/z) 310, 295, 253, 225, 196,
180, 154, 128, 84, 57. HRMS calcd for C20H42N2 310.3348,
found 310.3342.
4.2. General procedure for reductive amination of 1b–j
To a solution of N,N0-dimethyl cyclohexanediamine (1 g,
7 mmol) in methanol (15 mL) was added aldehyde
(21 mmol), sodium cyanoborohydride (28 mmol) and acetic
acid (7 mmol). The mixture was stirred 24 h, methanol was
then evaporated and the residue was diluted in ether
(20 mL). The organic layer was washed with sodium
hydroxide 10% (2!15 mL) and with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The product was purified by distillation, acid–base
extraction or column chromatography.
4.2.6. (1R,2R)-N,N0-Dibenzyl-N,N0-dimethyl-cyclohex-
ane-1,2-diamine 1g. The product was obtained according
to the general procedure, purified by distillation (bpZ
170 8C/1 mmHg) and isolated as a colorless oil in 49%
yield. 1H NMR: d(ppm) 1.05–1.35 (m, 4H), 1.7–1.8 (m, 2H),
1.9–2.0 (m, 2H), 2.24 (s, 6H), 2.6–2.7 (m, 2H), 3.68 (d, JZ
13.4 Hz, 2H), 3.76 (d, JZ13.1 Hz, 2H), 7.2–7.35 (m, 6H),
7.38–7.45 (m, 4H). 13C NMR: d(ppm) 25.8, 25.9, 36.2, 58.6,
63.7, 126.5, 127.9, 128.8, 140.9. [a]2D0Z C7.22 (c 1.02,
CHCl3). MS (m/z) 322, 257, 231, 200, 180, 160, 120, 91, 65.
HRMS calcd for C22H30N2 322.2409, found 322.2418.
4.2.1. (1R,2R)-N,N0-Dipropyl-N,N0-dimethyl-cyclohex-
ane-1,2-diamine 1b. The product was obtained according
to the general procedure, purified by distillation (bpZ80–
90 8C/0.1 mmHg) and isolated as a colorless oil in 68%
1
yield. H NMR: d(ppm) 0.86 (t, JZ7.32 Hz, 6H), 1.0–1.2
(m, 4H), 1.4–1.5 (m, 4H), 1.65–1.71 (m, 2H), 1.73–1.80 (m,
2H), 2.23 (s, 6H), 2.35–2.50 (m, 6H). 13C NMR: d(ppm)
12.1, 21.6, 25.7, 25.9, 36.6, 56.5, 63.1. [a]2D0Z K27.7
(c 1.0, CHCl3). MS (m/z) 226, 211, 183, 154, 152, 126, 112,
86, 70, 57. HRMS calcd for C14H30N2 226.2409, found
226.2408.
4.2.7. (1R,2R)-N,N0-Dimethyl-N,N0-diphenethyl-cyclo-
hexane-1,2-diamine 1h. The product was obtained accord-
ing to the general procedure, purified by distillation (bpZ
240 8C/1 mmHg) and isolated as a brown oil in 83% yield.
1H NMR: d(ppm) 1.05–1.30 (m, 4H), 1.65–1.75 (m, 2H),
1.78–1.88 (m, 2H), 2.35 (s, 6H), 2.52–2.62 (m, 2H), 2.70–
2.85 (m, 8H), 7.15–7.25 (m, 6H), 7.28–7.40 (m, 4H). 13C
NMR: d(ppm) 25.8, 25.9, 35.5, 36.6, 56.6, 63.5, 125.7,
128.1, 128.8, 141.1. [a]2D0Z K13.84 (c 1.0, CHCl3). MS
(m/z) 350, 259, 214, 155, 112, 70. HRMS calcd for
C24H34N2 350.2722, found 350.2737.
4.2.2. (1R,2R)-N,N0-Dibutyl-N,N0-dimethyl-cyclohexane-
1,2-diamine 1c. The product was obtained according to the
general procedure, purified by distillation (bpZ90–100 8C/
1
0.1 mmHg) and isolated as a colorless oil in 89% yield. H
NMR: d(ppm) 0.88 (t, JZ7.2 Hz, 6H), 1.0–1.2 (m, 4H),
1.2–1.48 (m, 8H), 1.63–1.69 (m, 2H), 1.72–1.78 (m, 2H),
2.21 (s, 6H), 2.38–2.52 (m, 6H). 13C NMR: d(ppm) 14.1,
20.8, 25.6, 25.9, 30.8, 36.6, 54.2, 63.0. [a]2D0Z K21.6
(c 0.99, CHCl3). MS (m/z) 254, 239, 211, 197, 166, 139,
126, 100, 84, 56. HRMS calcd for C16H34N2 254.2722,
found 254.2719.
4.2.8. (1R,2R)-N,N0-Dimethyl-N,N0-bis-(3-phenyl-pro-
pyl)-cyclohexane-1,2-diamine 1i. The product was
obtained according to the general procedure, purified by
distillation (bpZ190–210 8C/0.1 mmHg) and isolated as a
4.2.3. (1R,2R)-N,N0-Diisobutyl-N,N0-dimethyl-cyclohex-
ane-1,2-diamine 1d. The product was obtained according
to the general procedure, purified by distillation (bpZ80–
90 8C/0.1 mmHg) and isolated as a colorless oil in 72%
yield. 1H NMR: d(ppm) 0.88 (t, JZ6.2 Hz, 12H), 1.03–1.25
(m, 4H), 1.63–1.80 (m, 6H), 2.12–2.21 (m, 2H), 2.19 (s,
6H), 2.35–2.45 (m, 4H). 13C NMR: d(ppm) 20.9, 21.1, 26.0,
26.4, 26.8, 36.1, 63.8, 64.9. [a]2D0Z C23.4 (c 0.99, CHCl3).
1
yellow oil in 75% yield. H NMR: d(ppm) 1.05–1.25 (m,
4H), 1.68–1.75 (m, 2H), 1.76–1.90 (m, 6H), 2.28 (s, 6H),
2.50–2.72 (m, 10H), 7.18–7.25 (m, 6H), 7.28–7.33 (m, 4H).
13C NMR: d(ppm) 25.6, 25.7, 30.1, 33.8, 36.3, 54.1, 63.1,
125.5, 128.1, 128.3, 142.6. [a]2D0Z K6.7 (c 1.44, CHCl3).
MS (m/z) 378, 287, 230, 188, 149, 91. HRMS calcd for
C26H38N2 378.3035, found 378.3013.

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J.-C. Kizirian et al. / Tetrahedron 61 (2005) 8939–8946
4.2.9. (1R,2R)-N,N0-Dimethyl-N,N0-bis-(2,4,6-trimethyl-
benzyl)-cyclohexane-1,2-diamine 1j. The product was
obtained according to the general procedure, purified by
acid–base treatment and isolated as a solid in 87% yield. 1H
NMR: d(ppm) 1.10–1.26 (m, 4H), 1.75–1.82 (m, 2H), 1.87
(s, 6H), 1.96–2.04 (m, 2H), 2.27 (s, 6H), 2.38 (s, 12H), 2.40–
2.47 (m, 2H), 3.48 (d, JZ12.6 Hz, 2H), 3.72 (d, JZ12.9 Hz,
2H), 6.81 (s, 4H). 13C NMR: d(ppm) 20.0, 20.9, 24.6, 26.1,
34.0, 52.5, 61.1, 128.7, 133.6, 135.8, 138.2. [a]2D0Z K16.7
(c 0.88, CHCl3). MS (m/z) 406, 302, 273, 202, 163, 133, 91.
HRMS calcd for C28H42N2 406.3348, found 406.3329.
purified by silica gel column chromatography to give the
pure product.
4.3.1. (4-Methoxy-phenyl)-(1-phenyl-ethyl)-amine 8. The
mixture was stirred 15 h before the quench. The product was
purified by silica gel chromatography to give the product as
a yellow oil. 1H NMR: d(ppm) 1.49 (d, JZ6.8 Hz, 3H), 3.68
(s, 3H), 4.39 (q, JZ6.8 Hz, 1H), 6.46 (d, JZ9.0 Hz, 2H),
6.70 (d, JZ9.0 Hz, 2H), 7.1–7.5 (m, 5H). 13C NMR: d(ppm)
25.2, 54.3, 55.8, 114.6, 114.8, 125.9, 126.9, 128.7, 141.6,
145.6, 151.9. Enantiomeric excess was determined by SFC
Chiralcel OD-H, 200 bar, 2 mL minK1, 2% MeOH in CO2,
30 8C, R t1Z9.26 min, S t2Z9.84 min. Chiralcel OB-H,
200 bar, 2 mL minK1, 15% MeOH in CO2, 30 8C, S t1Z
6.77 min, R t2Z12.31 min.
4.2.10. Bis-(tert-butyl)-cyclohexane-1,2-diamide 6. (R,R)-
1,2-Diammoniumcyclohexane mono-(C)-tartrate salt (2 g,
7.6 mmol) was dissolved in water (5 mL) with sodium
hydroxide (600 mg, 15.2 mmol) and pivaloyl chloride
(9.3 mL, 76 mmol) was added while the mixture was heated
at 40 8C. After stirring 3 h at this temperature, the solution
was quenched with sodium hydroxide until basic pH and
extracted with dichloromethane. The combined organic
layer was dried over Na2SO4 and solvent are evaporated.
The solid was diluted in ether and insoluble impurities were
filtered. After evaporation under reduced pressure, the bis-
(tert-butyl)-cyclohexane diamide was isolated in 70% yield.
1H NMR: d(ppm) 1.17 (s, 18H), 1.20–1.45 (m, 4H), 1.68–
1.82 (m, 2H), 2.0–2.11 (m, 2H), 3.60–6.38 (m, 2H), 6.17 (br
s, 2H). 13C NMR: d(ppm) 24.7, 27.5, 32.4, 38.5, 53.6, 179.1.
4.3.2. (2-Methoxy-phenyl)-(1-phenyl-ethyl)-amine 11.
The mixture was stirred 2 h before the quench. The residue
was purified by silica gel column chromatography (toluene)
to give the product as a yellow oil. 1H NMR: d(ppm) 1.61 (d,
JZ6.6 Hz, 3H), 3.93 (s, 3H), 4.53 (q, JZ6.7 Hz, 1H), 4.6–
4.85 (s, 1H), 6.41 (dd, J1Z7.8 Hz, J2Z1.5 Hz, 1H), 6.67
(dt, J1Z7.6 Hz, J2Z1.5 Hz, 1H), 6.76 (dt, J1Z7.6 Hz, J2Z
1.5 Hz, 1H), 6.82 (dd, J1Z7.8 Hz, J2Z1.5 Hz, 1H), 7.25–
7.30 (m, 1H), 7.37 (t, JZ7.8 Hz, 1H), 7.41–7.45 (m, 1H).
13C NMR: d(ppm) 25.1, 53.3, 55.3, 109.2, 111.0, 116.3,
121.1, 125.8, 126.7, 128.5, 137.1, 145.4, 146.5. Enantio-
meric excess was determined by SFC Chiralcel OD-H,
200 bar, 2 mL minK1, 2% MeOH in CO2, (2%, 6 min, 1%
minK1, 15%), 30 8C, t1Z5.58 min, t2Z7.90 min.
4.2.11. (1R,2R)-N,N0-Bis-(2,2-dimethyl-propyl)-N,N0-
dimethyl-cyclohexane-1,2-diamine 1k. To a suspension
of LAH (4.8 g, 0.13 mmol) in THF (50 mL) was added bis-
(tert-butyl)-cyclohexane diamide 6 (3.55 g, 0.013 mmol)
and the mixture was refluxed 2 weeks. The solution was
cooled to room temperature, poured into crushed ice and
extracted with ether. The combined organic layer was dried
over Na2CO3, filtered and concentrated to give the crude
diamine as a solid, which was methylated without
purification. The diamine (1.2 g, 4.7 mmol) was dissolved
in formic acid 85% (2.3 mL), formaldehyde 40% (1.9 mL)
was added and the mixture was refluxed 3 h. After
basification and extraction with ether, the organic layer
was dried over Na2SO4, filtered and concentrate. The
residue was purified by bulb-to-bulb distillation (120 8C/
1 mmHg) to give the product as a colorless oil in 72% yield.
1H NMR: d(ppm) 0.90 (s, 18H), 1.03–1.12 (m, 2H), 1.17–
1.30 (m, 2H), 1.64–1.70 (m, 2H), 1.73–1.80 (m, 2H), 2.25–
2.40 (m, 12H). 13C NMR: d(ppm) 26.1, 27.1, 28.6, 33.3,
38.7, 66.6, 70.0. [a]D20Z C6.3 (c 1.03, CHCl3). MS (m/z)
282, 225, 169, 124, 114, 58. HRMS calcd for C18H38N2
282.3035, found 282.3024.
4.3.3. (2-Isopropyl-phenyl)-(1-phenyl-ethyl)-amine 12.
The mixture was stirred 2 h before the quench. The residue
was purified by silica gel column chromatography (toluene)
to give the product as a yellow oil. RFZ0.61 (cyclohexane/
1
etherZ95:5). H NMR: d(ppm) 1.47 (d, JZ6.8 Hz, 6H),
1.69 (d, JZ6.8 Hz, 3H), 3.12 (sept, JZ6.8 Hz, 1H), 4.0–4.3
(br s, 1H), 4.67 (q, JZ6.8 Hz, 1H), 6.55 (dd, J1Z1.0 Hz,
J2Z8.3 Hz, 1H), 6.83 (dt, J1Z1.0 Hz, J2Z7.6 Hz, 1H),
7.09 (dt, J1Z1.8 Hz, J2Z7.6 Hz, 1H), 7.26–7.55 (m, 6H).
13C NMR: d(ppm) 22.2, 22.3, 25.25, 27.3, 53.35, 111.6,
117.1, 124.7, 125.7, 126.5, 126.75, 128.6, 131.6, 143.7,
145.3. Enantiomeric excess was determined by SFC
Chiralcel OJ, 200 bar, 2 mL minK1, 2% MeOH in CO2,
(2%, 6 min, 1% minK1, 15%), 30 8C, t1Z5.12 min, t2Z
6.00 min. [a]2D0Z K29.5 (c 1.25, CHCl3, eeZ20% with 1f).
MS (m/z) 239, 224, 182, 134, 105, 91, 51. HRMS calcd for
C17H21N 239.1674, found 239.1686.
4.3.4. (4-Methoxy-phenyl)-(1-p-tolyl-ethyl)-amine 13a.
The mixture was stirred 12 h before the quench. The residue
was purified by silica gel column chromatography (pentane/
4.3. Asymmetric addition of MeLi to imines. General
procedure
1
etherZ10:1) to give the product as a yellow oil. H NMR:
d(ppm) 7.17 (d, 2H, JZ7.8 Hz), 7.04 (d, 2H, JZ7.8 Hz),
6.61 (d, 2H, JZ9.0 Hz), 6.39 (d, 2H, JZ9.0 Hz), 4.30 (q,
1H, JZ6.6 Hz), 3.80–3.62 (br s, 1H), 3.61 (s, 3H), 2.24 (s,
3H), 1.40 (d, 3H, JZ6.6 Hz). 13C NMR: d(ppm) 151.8,
142.5, 141.7, 136.3, 129.3, 125.8, 114.5, 55.7, 53.9, 25.2,
21.1. Enantiomeric excess was determined by SFC
Chiralpak AS-H, 200 bar, 2 mL minK1, 5% MeOH in
CO2, (5%, 5 min, 1% minK1, 20%), 30 8C, t1Z3.34 min,
t2Z4.47 min. MS (m/z) 241, 226, 119, 108, 91, 65. HRMS
calcd for C16H19NO 241.1466, found 241.1462.
To a cooled (K78 8C) stirred solution of imine (0.48 mmol)
and diamine ligand (0.096 or 0.96 mmol), in dry toluene
(8 mL) under an inert atmosphere, was added an ether
solution of MeLi (low halide, 1.6 M in ether, 1.44 mmol)
over a period of 5 min. The mixture was stirred at K78 8C
for the time indicated and quenched with methanol (1 mL)
at deep temperature and with water (5 mL) at room
temperature. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was

J.-C. Kizirian et al. / Tetrahedron 61 (2005) 8939–8946
8945
4.3.5. [1-(4-Chloro-phenyl)-ethyl]-(4-methoxy-phenyl)-
amine 13b. The mixture was stirred 12 h before the quench.
The residue was purified by silica gel column chromato-
graphy (pentane/etherZ10:1) to give the product as a
yellow oil. 1H NMR: d(ppm) 7.35–7.30 (m, 4H), 6.74
(d, 2H, JZ9.1 Hz), 6.48 (d, 2H, JZ9.1 Hz), 4.42 (q, 1H,
JZ6.8 Hz), 3.83–3.74 (br s, 1H), 3.74 (s, 3H), 1.51 (d, 3H,
JZ6.8 Hz). 13C NMR: d(ppm) 152.3, 132.5, 129.8, 128.8,
127.4, 114.9, 114.8, 114.0, 55.7, 54.1, 25.0. Enantiomeric
excess was determined by SFC Chiralpak AD, 200 bar,
13f. The mixture was stirred 15 h before the quench. The
residue was purified by silica gel column chromatography
1
to give the product as a yellow oil. H NMR: d(ppm) 1.53
(d, JZ6.6 Hz, 3H), 3.69 (s, 3H), 4.1 (br s, 1H), 4.55 (q, JZ
6.8 Hz, 1H), 6.53 (d, JZ8.8 Hz, 2H), 6.71 (d, JZ9.1 Hz,
2H), 7.12 (m, 1H), 7.34 (d, JZ7.8 Hz, 1H), 7.59 (dt, J1Z
1.8 Hz, J2Z7.6 Hz, 1H), 8.57 (d, JZ4.8 Hz, 1H). 13C
NMR: d(ppm) 23.3, 55.6, 55.7, 114.75, 114.8, 120.4, 121.9,
136.8, 141.4, 149.3, 152.0, 164.2. Enantiomeric excess was
determined by SFC Chiralcel OJ, 200 bar, 2 mL minK1, 5%
MeOH in CO2, (5%, 6 min, 1% minK1, 15%), 30 8C, t1Z
8.58 min, t2Z10.45 min.
2 mL minK1, 5% MeOH in CO2, (5%, 5 min, 1% minK1
,
20%), 30 8C, t1Z7.56 min, t2Z8.61 min, and Chiralpak
AS-H, 200 bar, 2 mL minK1, 5% MeOH in CO2, (5%,
5 min, 1% minK1, 20%), 30 8C, t1Z4.65 min, t2Z5.86 min.
[a]2D0Z C15.0 (c 0.93, CHCl3, eeZ68% with 1h). MS (m/z)
4.3.10. (4-Methoxy-phenyl)-(2-naphtalen-2-yl-ethyl)-
amine 13g. The mixture was stirred 35 h before the quench.
The residue was purified by silica gel column chromato-
graphy (pentane/etherZ10:1) to give the product as a
yellow oil. 1H NMR: d(ppm) 7.73–7.70 (m, 4H), 7.42
(d, JZ8.6 Hz, 1H), 7.39–7.32 (m, 2H), 6.59 (d, JZ8.8 Hz,
2H), 6.43 (d, JZ8.8 Hz, 2H), 4.48 (q, 1H, JZ6.6 Hz), 4.35–
3.65 (br s, 1H), 3.58 (s, 3H), 1.49 (d, 3H, JZ6.6 Hz). 13C
NMR: d(ppm) 152.0, 142.9, 141.4, 133.6, 132.7, 129.1,
128.4, 127.8, 127.7, 126.0, 125.5, 124.5, 124.4, 114.8, 55.7,
54.6, 25.1. Enantiomeric excess was determined by SFC
Chiracel OD-H, 175 bar, 2 mL minK1, 2% MeOH in CO2,
(2%, 20 min), 30 8C, t1Z8.36 min, t2Z8.72 min.
261, 246, 139, 123, 108, 77, 52. HRMS calcd for
C15H ClNO 261.0920, found 261.0921. HRMS calcd for
35
16
37
C15H ClNO 263.0890, found 263.0902.
16
4.3.6. (4-Methoxy-phenyl)-[1-(4-trifluoromethyl-phenyl)-
ethyl]-amine 13c. The mixture was stirred 12 h before the
quench. The residue was purified by silica gel column
chromatography (pentane/etherZ10:1) to give the product
as a yellow oil. RFZ0.22 (eluent:pentane/etherZ10:1). 1H
NMR: d(ppm) 7.49 (d, 2H, JZ8.2 Hz), 7.40 (d, 2H, JZ
8.2 Hz), 6.61 (d, 2H, JZ8.8 Hz), 6.34 (d, 2H, JZ8.8 Hz),
4.37 (q, 1H, JZ6.7 Hz), 3.78–3.75 (br s, 1H), 3.60 (s, 3H),
1.42 (d, 3H, JZ6.7 Hz). 13C NMR: d(ppm) 152.3, 149.8,
141.0, 126.2, 125.7, 125.6, 125.6, 114.9, 114.6, 55.7, 54.1,
25.1. Enantiomeric excess was determined by SFC
Chiralpak AD, 200 bar, 2 mL minK1, 5% MeOH in CO2,
(5%, 5 min, 1% minK1, 20%), 30 8C, t1Z3.27 min, t2Z
3.64 min. [a]2D0Z K4.3 (c 0.91, CHCl3, eeZ58% with 1h).
MS (m/z) 295, 280, 173, 122, 95, 77. HRMS calcd for
C16H16F3NO 295.1184, found 295.1186.
4.3.11. (1-Benzo[1,3]dioxol-5-yl-ethyl)-(4-methoxy-
phenyl)-amine 13h. The mixture was stirred 14 h at
K30 8C before the quench. The residue was purified by
silica gel column chromatography (pentane/etherZ10:1) to
give the product as a yellow oil. 1H NMR: d(ppm) 6.79–6.74
(m, 2H), 6.68–6.61 (m, 3H), 6.40 (d, JZ8.8 Hz, 2H), 5.84
(d, JZ5.3 Hz, 2H), 4.25 (q, JZ6.6 Hz, 1H), 3.80–3.50 (br s,
1H), 3.62 (s, 3H), 1.38 (d, JZ6.6 Hz, 3H). 13C NMR:
d(ppm) 151.9, 147.9, 146.3, 141.5, 139.7, 118.9, 114.7,
114.5, 108.3, 106.3, 100.9, 55.7, 54.1, 25.4. Enantiomeric
excess was determined by SFC Chiralcel OD-H, 200 bar,
4.3.7. (1-Furan-2-yl-ethyl)-(4-methoxy-phenyl)-amine
13d. The mixture was stirred 15 h before the quench. The
residue was purified by silica gel column chromatography
(pentane/etherZ10:1) to give the product as a yellow oil.
1H NMR: d(ppm) 1.54 (d, JZ6.6 Hz, 3H), 3.74 (s, 3H), 4.55
(q, JZ6.6 Hz, 1H), 6.14 (d, JZ3.3 Hz, 1H), 6.28 (dd, J1Z
1.7 Hz, J2Z3.0 Hz, 1H), 6.61 (d, JZ8.8 Hz, 2H), 6.76
(d, JZ8.8 Hz, 2H), 7.33 (dd, J1Z0.8 Hz, J2Z1.8 Hz, 1H).
13C NMR: d(ppm) 20.9, 48.3, 55.7, 105.0, 110.0, 114.7,
115.1, 141.1, 141.35, 152.4, 157.4. Enantiomeric excess
was determined by SFC Chiralcel OD-H, 200 bar,
2 mL minK1, 5% MeOH in CO2, (5%, 5 min, 1% minK1
,
20%), 30 8C, t1Z6.76 min, t2Z7.28 min, and Chiralcel OJ,
200 bar, 2 mL minK1, 5%, 5 min, 1% minK1, 20%), 30 8C,
t1Z11.5 min, t2Z12.4 min. [a]2D0Z C12.7 (c 1.1, CHCl3,
eeZ48% with 1h). MS (m/z) 271, 149, 123, 108, 91, 65.
HRMS calcd for C16H17NO3 271.1208, found 271.1202.
Acknowledgements
2 mL minK1, 2% MeOH in CO2, (2%, 6 min, 1% minK1
,
10%), 30 8C, t1Z5.82 min, t2Z6.24 min.
The authors wish to thank PPG-SIPSY for financial support,
Du Pont de Nemours GmbH for a generous gift of
´ `
cyclohexane diamine, Segolene Gille and Iain Rudkin for
fruitfull discussions.
4.3.8. (4-Methoxy-phenyl)-(1-thiophen-2-yl-ethyl)-amine
13e. The mixture was stirred 15 h before the quench. The
residue was purified by silica gel column chromatography
1
to give the product as a yellow oil. H NMR: d(ppm) 1.64
(d, JZ6.6 Hz, 3H), 3.76 (s, 3H), 4.78 (q, JZ6.6 Hz, 1H),
6.63 (d, JZ9.1 Hz, 2H), 6.79 (d, JZ9.1 Hz, 2H), 6.96–7.02
(m, 2H), 7.20 (dd, J1Z1.4 Hz, J2Z4.9 Hz, 1H). 13C NMR:
d(ppm) 24.6, 50.4, 55.6, 114.7, 115.0, 122.8, 123.5, 126.6,
141.0, 150.4, 152.3. Enantiomeric excess was determined
by SFC Chiralcel OD-H, 200 bar, 2 mL minK1, 2% MeOH
in CO2, (2%, 20 min), 30 8C, t1Z9.48 min, t2Z10.06 min.
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