Simple 1,2-diamine ligands for asymmetric addition of aryllithium reagents to imines

Article abstract of DOI:10.1002/ejoc.200500447

Enantioselective addition of various aryllithium reagents to aromatic imines was catalyzed (20 mol-%) by readily accessible 1,2-diamines to afford a wide range of protected diarylmethylamines in up to 94 % enantiomeric excess. Furthermore, the absolute configuration of these arylation products was determined by using X-ray crystallography. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500447

FULL PAPER
Simple 1,2-Diamine Ligands for Asymmetric Addition of Aryllithium Reagents
to Imines
Noemi Cabello,[a] Jean-Claude Kizirian,[a] Ségolène Gille,[a] Alexandre Alexakis,*[a]
Gérald Bernardinelli,[a] Laurent Pinchard,[b] and Jean-Claude Caille[b]
Keywords: Diamines / Asymmetric 1,2-addition / Imines / Organolithium compounds
Enantioselective addition of various aryllithium reagents to
aromatic imines was catalyzed (20 mol-%) by readily access-
ible 1,2-diamines to afford a wide range of protected diaryl-
methylamines in up to 94% enantiomeric excess. Further-
more, the absolute configuration of these arylation products
was determined by using X-ray crystallography.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
aromatic imines using a wide diversity of aryllithium rea-
gents activated by readily accessible chiral 1,2-diamines.[7]
The stereochemical outcome of the reaction has been estab-
lished by a single X-ray analysis of an N-p-methoxyphenyl-
diarylmethylamine adduct [(–)-16, see text].
Introduction and Background
Chiral amines are compounds of great interest in organic
synthesis since they constitute building blocks for complex
structures of biologically active molecules, as well as being
employed as chiral auxiliaries, ligands, or agents for kinetic
resolution.[1] The addition of aliphatic organometallic com-
pounds to the azomethine bond of activated imines is now
a route of choice for synthesizing aliphatic amines and aryl- Results and Discussion
alkylamines in excellent yields and enantioselectivities.[2] By
Recently, we described the synthesis of new chiral tertiary
contrast, the asymmetric addition of aromatic compounds
to imines affording diarylmethylamines has been scarcely
reported, although this backbone can be found in different
drugs such as cetirizine or the non-peptidic γ-opioid agonist
SNC-80.[3] In 1990 Tomioka and coworkers described the
first enantioselective addition of an aryllithium compound
to aromatic imines promoted by an external chiral ligand,
but despite this work,[4] only a few efficient examples of
such arylation processes were reported in the nineties. Nev-
ertheless, since 2000, this is a topic of growing interest. The
most remarkable examples in terms of enantioselectivity in-
clude the diphenylzinc addition to N-formylimines reported
by Bräse et al. in 2002[5] and the work of Hayashi et al.[6]
They described in 2000 a highly enantioselective rhodium-
catalyzed arylation of N-alkylidenesulfonamides with or-
ganostannanes, and very recently a more environmentally
friendly procedure involving the addition of arylboroxines
to different imines with enantioselectivities of up to 99%.[6]
All of these procedures are indeed high yielding and selec-
tive, but they suffer from the cost of the catalysts used. We
report herein a low cost and efficient catalytic arylation of
1,2-diamines 1a–f (Scheme 1) and their use in the addition
of organolithium compounds to N-p-methoxyphenyl-
imines.[8] Herein, we wish to present the results obtained for
the addition of aryllithium reagents to these types of imines
(Table 1). Bearing in mind that only a few examples have
been reported to date on this topic, our preliminary study
and optimization of the conditions were carried out with
imine 2, the substrate used by Tomioka and co-workers in
1994.[9] They reported that in the presence of a stoichiomet-
ric amount of diether 4, product 3 was obtained in 87% ee
with the absolute configuration S.[9] We found that the same
reaction afforded 3 in 86% ee (Entry 7). As also mentioned
by these authors, we noticed that only toluene and diethyl
ether were suitable solvents for the enantioselective version
of the reaction. Indeed, in more coordinating solvents such
as THF, the reaction proceeded well, but afforded a racemic
product. When the reaction was carried out with our di-
amine ligands, poorer levels of enantioselectivity were in-
duced, particularly with hindered ligands, in contrast with
the results obtained for the previously reported addition of
methyllithium to imines.[8] It has to be noted at this point
that the best result (54% ee, Entry 1) was reached with the
simplest (R,R)-(–)-N,N,NЈ,NЈ-tetramethyl-trans-1,2-cyclo-
hexanediamine (1a), readily prepared by the Eschweiler–
Clark methylation of the readily available (R,R)-1,2-diam-
moniumcyclohexane mono-(+)-tartrate.[10]
[a] Department of Organic Chemistry, University of Geneva,
30 quai Ernest Ansermet, 1211 Genève 4, Switzerland
Fax: +41-22-328-73-96
E-mail: alexandre.alexakis@chiorg.unige.ch
[b] PPG-SIPSY, Z. I.,
La croix cadeau, B. P. 79, 49242 Avrille Cedex, France
Eur. J. Org. Chem. 2005, 4835–4842
DOI: 10.1002/ejoc.200500447
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4835

A. Alexakis et al.
FULL PAPER
Scheme 2.
Table 2. Addition of phenyllithium to imines 5a and 5b.
Entry Ligand
Product Isolated yield ee (%)[a]
Scheme 1.
(0.2 equiv.)
(%)
Table 1. Addition of phenyllithium to imine 2.
1
2
3
4
5
6
1a (2 equiv.)
6a
6a
6b
6a
6a
6a
69
95
87
68
62
62
58 (+)
60 (+)
20 (–)
3
12
7 (+)
Isolated yield (%) ee (%)[a]
1a
Entry
Ligand
1a
1
2
3
4
5
6
7
8
1a
72
60
61
34
44
79
49
50
54 (R)
19 (R)
0
11 (R)
43 (R)
19 (R)
86 (S)[b]
23 (R)
1c
1b
1e
1c
4 (2 equiv.)
(–)-sparteine
(2 equiv.)
(–)-sparteine
7a
1d
7
6a
60
44 (–)
1e
1f
8
9
10
11
6a
6a
6a
6a
79
82
87
81
0
4
61 (–)
59 (–)
28 (+)
(–)-sparteine
7b
7c
[a] Enantiomeric excesses were determined by supercritical fluid
chromatography (SFC), column Chiralcel OB-H. The absolute con-
figuration was established by comparison of the SFC chromato-
gram with the one obtained in entry 7 (see ref.[9]). [b] 87% ee was
reported by Tomioka et al. (see ref.[9]).
[a] Enantiomeric excesses were determined by SFC, columns Chi-
ralcel OJ for 6a and Chiralcel AD-H for 6b. Signs in parenthesis
refer to the optical rotations.
When employing aromatic imines 5a and 5b as substrates
The influence of an α-heteroatom could clearly be seen
(Scheme 2),[11] with the expectation that this system is more from the comparison of thienyl imine 5a and furyl imine
suitable than imine 2 for our diamine ligands, a different 5b. Thienyl imine 5a behaves like other aryl imines (see
trend was observed. We found that under stoichiometric Table 3), with 60% ee (Table 2, Entry 2), whereas furyl im-
conditions, and at –78 °C, an enantiomeric excess of 58% ine 5b affords a low 20% ee (Table 2, Entry 3). Thus, in
was obtained with the addition of phenyllithium to imine contrast to oxygen, sulfur does not seem to compete with
5a with diamine 1a (Table 2, Entry 1), versus 44% with the diamine catalyst for coordination to lithium. The low
(–)-sparteine (Entry 7) and only 7% with diether 4 (Entry ee may be ascribed to this oxygen–lithium coordination.
6). Moreover, under substoichiometric conditions, the level
Table 3 shows the generalization of the method. With
of enantioselectivity remained unchanged with 0.2 equiv. of aromatic imines 9–11 (Scheme 3, Table 3) we could also
ligand 1a per mol of imine (Entry 2), whereas such catalysis evaluate the effect of the electronic character of the sub-
was not possible with (–)-sparteine (Entry 8). It should be strate. These results reveal that the electronic effect of the
pointed out that, in the toluene solvent, the reaction is aromatic part of the imines 9–11 is low. Good yields were
rather sluggish in the absence of diamine. For example, the obtained in all cases with enantioselectivities between 60–
synthesis of the racemic adducts was performed at room 70%. Thus, a typical electron-withdrawing group, such as
temperature, otherwise the conversions were very low. Good trifluoromethyl (imine 9d, Entry 9) afforded an ee of 60%,
induction was also obtained with ligands 7a [prepared from whereas a typical electron-donating group, such as methoxy
readily available (1S,2S)-N-methylpseudoephedrine follow- (imine 9b, Entry 7) gave a higher ee of 68%. Only product
ing the procedure of Dieter][12] and 7b[13] (61% and 59% 14 presented a slightly lower ee of 55% (Entry 14), perhaps
ee, respectively, Entries 9 and 10). In both cases, the major due to a steric hindrance of the 1-naphthyl group. Once
enantiomer was the opposite one to that obtained with li- again, an efficient catalysis with ligand 1a was possible,
gand 1a. The effect of the configuration of each stereocen- while it was not with (–)-sparteine (compare Entries 2 and
ter of the 1,2-diamine ligand on the enantioselectivity was 4). The efficiency of the catalysis was tested further with
pointed out by using 7c [prepared from (1R,2S)-N-methyl- only 10 and 5 mol-% of the diamine ligand. Despite the
ephedrine following the procedure of Dieter][12] as the cata- slightly lower conversions, the enantioselectivities remained
lyst (Entry 11).
almost unchanged (Entries 9–11).
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Asymmetric Addition of Aryllithium Reagents to Imines
FULL PAPER
Table 3. Addition of phenyllithium to imines 9–11.[a]
Entry
Imine
Ligand
Product
% Conversion[b]
(% isolated yield)
ee (%)[c]
1
2
3
4
5
6
7
8
9a
9a
9a
9a
9a
9b
9b
9c
9d
9d
9d
9e
10
11
1a (3 equiv.)
12a
12a
12a
12a
12a
12b
12b
12c
12d
12d
12d
12e
13
Ͼ99 (64)
62 (42)
88 (72)
39 (23)
Ͼ99 (72)
79 (78)
26 (14)
58 (42)
Ͼ99 (72)
97 (90)
93 (86)
48 (44)
77 (74)
79 (61)
64 (+)
62 (+)
59 (–)[d]
2
28 (+)
69 (–)
68 (–)
63 (–)
60 (+)
56 (+)
53 (+)
64 (–)
61 (–)
55 (+)
1a (0.2 equiv.)
(–)-sparteine (3 equiv.)
(–)-sparteine (0.2 equiv.)
4 (3 equiv.)
1a (3 equiv.)
1a (0.2 equiv.)
1a (0.2 equiv.)
1a (0.2 equiv.)
1a (0.1 equiv.)
1a (0.05 equiv.)
1a (0.2 equiv.)
1a (0.2 equiv.)
1a (0.2 equiv.)
9
10
11
12
13[e]
14
14
[a] All reactions were carried out at –78 °C in toluene as the solvent for 4 h, unless otherwise stated. [b] Conversions evaluated by 1H
NMR spectroscopy of the crude. [c] Enantiomeric excesses were determined by SFC, columns Chiralpak AS-H for 12a and 12d, Chiralcel
OJ for 12b and Chiralcel OD-H for 12c, 12e, 13 and 14. Signs in parenthesis refer to the optical rotations. [d] Reported in 50% ee under
stoichiometric conditions by Senanayake (see ref.[3b]). [e] Reaction time: 2.5 h.
general, the enantioselectivities induced by ligand 1a were
similar to those described above, despite the higher tem-
peratures needed in some cases, to obtain reasonable yields
(Table 4). Interestingly, the ee of 14 reached an exception-
ally good 90% ee with the addition of 1-naphthyllithiun to
imine 8 (Entry 6).
Scheme 3.
One of the advantages of this approach is that by simply
changing the imine/organolithium partner, either enantio-
mer can be produced. Indeed amines 6a and 6b could be
obtained by addition of thienyl and furyllithium to imine
8, formed in situ by deprotonation of furane and thiophene
with nBuLi (Scheme 4). Amines 12a, 12b, 13 and 14 were
formed by addition of the corresponding aryllithium rea-
gents, obtained by metal–halogen exchange of the appropri-
ate aryl halides and nBuLi (for details see Exp. Sect.). In Scheme 4.
Table 4. Addition of aryllithium compounds to imine 8.
Entry
1
Conditions
Ar in ArLi
2-Thienyl
Product
Isolated yield (%)
71
ee (%)[a,b]
1a (2 equiv.), toluene,
–20 °C, 15 h
1a (2 equiv.), Et2O,
–78 °C to room temp.
1a (2 equiv.), toluene,
–78 °C, 4 h
1a (2 equiv.), toluene,
–78 °C, 2 h
1a (2 equiv.), toluene,
78 °C, 2 h
6a
58 (–)
[58 (+)]
28 (+)
[20 (–)]
69 (–)
[64 (+)]
62 (+)
[69 (–)]
67 (+)
[61 (–)]
90 (–)
2
3
4
5
6
2-Furyl
6b
45
76
93
98
98
4-ClC6H4
4-MeOC6H4
2-naphthyl
1-naphthyl
12a
12b
13
1a (2 equiv.), toluene,
–78 °C, 2 h
14
[55 (+)]
[a] Enantiomeric excesses were determined by SFC Columns Chiralcel OJ for 6a and 12b, Chiralcel AD-H for 6b, Chiralpak AS-H for
12a and Chiralcel OD-H for 13 and 14. Signs in parenthesis refer to the optical rotations. [b] The enantiomeric excesses of the addition
of phenyllithium to imines, from Table 2 and Table 3 are indicated in brackets.
Eur. J. Org. Chem. 2005, 4835–4842
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A. Alexakis et al.
FULL PAPER
In order to study the interesting case of 1-naphthyllith- improvements. Thus we tested the addition of 1-naph-
ium more thoroughly, the addition was carried out on other thyllithium to imine 8 in the presence of 0.2 equiv. of 1a or
imines (Scheme 5, Table 5), as done previously for phen- 7a and were gratified to obtain respectively, 84% and 80%
yllithium. However, a dramatic difference of reactivity be- ee (Entries 2 and 4). These good results with substoichi-
tween these two aryllithium compounds was observed. ometric amounts of ligands that are so easy to prepare are
While the addition of phenyllithium to imine 9a was com- providing a future for this procedure in the arylation of
plete in 4 h at –78 °C (Table 3, Entry 1), a conversion of imines.
only 15% after 6 h was reached for the addition of 1-naph-
Since the interchange of aryl imines and aryllithiums
thyllithium, but with a very good ee of 89% (Table 5, Entry produces opposite enantiomers, it is clear that any arylli-
7). Similarly, with the less reactive imine 9e, at –78 °C after thium attacks the same prochiral face of any aryl imine. To
7 h, no reaction was detected. Different temperatures were determine this facial selectivity, it was necessary to know
tested, and good yields were obtained at temperatures near the absolute stereochemistry of our adducts. Thus, the abso-
to –40 or –50 °C without any significant loss of enantio- lute configuration of the major enantiomer of (–)-16 could
selectivity (Entries 13–15). Moreover, when (–)-sparteine be determined by X-ray crystallography. Indeed, this amine
was tested as the ligand, poor enantioselectivities and yields was obtained in 89% ee by addition of 1-naphthyllithium
were obtained (compare Entries 10 and 8). Ligand 7a af- to imine 8 in Et2O as solvent and in the presence of 2 equiv.
forded compound 14 in a 94% ee, one of the highest of 1a (Entry 9). After usual purification by column
enantioselectivities reported for this kind of reaction (Entry chromatography, the amine was obtained as a white solid
3). As we stated in the introduction, the achievement of and crystals suitable for X-ray analysis were obtained from
a substoichiometric version of this promising asymmetric a mixture of pentane/Et2O. We determined the configura-
reaction would be the key to new perspectives and future tion to be R [Flack parameter x = –0.01 (9)].[14] CD spectra
of both (–)-16 and the crystal analyzed by X-ray crystal-
lography were of the same sign, therefore confirming the R
configuration of (–)-16. 1-naphthyllithium activated by 1a
thus attacks the Si face of the imine. It seems reasonable to
assume that the same stereochemical pathway is followed
by all the other aryllithium reagents. Although the Si face
is attacked, the actual absolute configuration may vary ac-
cording to the CIP priority rules.
Conclusions
In summary, a wide variety of N-protected diarylmethyl-
amines, in both enantiomeric forms, were synthesized with
Scheme 5.
enantiomeric excesses of up to 94% by addition of aryl-
Table 5. Addition of 1-naphthyllithium to different imines.
Entry
R
Imine Product
Ligand
Conditions[a]
% Conversion[b]
(% isolated yield)
ee (%)[c]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
C6H5
C6H5
C6H5
C6H5
2-MeC6H4
2-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
8
14
14
14
14
15
15
16
16
16
16
17
17
18
18
18
1a
–78 °C, 2 h
–78 °C, 4 h
–78 °C, 2 h
–78 °C, 9 h
–41 °C, 3 d[f]
–25 °C, 5 d[f]
–78 °C, 6 h
–65 °C, 21 h
–65 °C, 21 h[h]
–67 °C, 13 h
–55 °C, 3 d[f]
–55 °C, 3 d[f]
–55 °C, 3 d[f]
–41 °C, 3 d[f]
–25 °C, 4 d[f]
Ͼ99 (98)
19
70 (45)
57
Ͼ99
Ͼ99
15
Ͼ99 (64)
67
90 (–)
8
1a (0.2 equiv.)
84 (–)[e]
94 (+)
80 (+)
86 (–) (Ͼ98)[g]
94 (+)
89 (–)
8
8
7a
7a (0.2 equiv.)
9f
9f
9a
9a
9a
9a
9c
9c
9e
9e
9e
1a
7a
1a
1a
90 (–)
1a
89 (–) (R)[i]
10
4-ClC6H4
(–)-sparteine
50
4-MeC6H4
4-MeC6H4
3,4-(OCH2O)-C6H3
3,4-(OCH2O)-C6H3
3,4-(OCH2O)-C6H3
1a
7a
1a
1a
7a
Ͼ99 (66)
28 (28)
20
Ͼ99 (60)
Ͼ99 (90)
88 (–)
92 (+)
90 (–)
86 (–)
90 (+)
[a] Unless otherwise indicated, all reactions were carried out in toluene and in the presence of 2 equiv. of the ligand. [b] Conversions
1
evaluated by H NMR spectroscopy of the crude. [c] Enantiomeric excesses were determined by SFC Columns Chiralcel OD-H for 14
and 18 and OJ for 15–17. Signs in parenthesis refer to the optical rotations. [d] From Table 4. [e] Average of two runs. [f] Nonoptimized
reaction times. [g] In parenthesis, enantiomeric excess after recrystallization in Pentane/Et2O. [h] Experiment carried out in Et2O. [i] Deter-
mined by X-ray analysis.
4838
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Eur. J. Org. Chem. 2005, 4835–4842

Asymmetric Addition of Aryllithium Reagents to Imines
FULL PAPER
product was isolated in 75% yield as a yellow oil of [α]2D0 = –31.3
(c = 1.01, CHCl3) and was used without further purification. Spec-
tral data were in agreement with the literature.[24]
lithium compounds to aromatic imines catalyzed by readily
available 1,2-diamine ligands. The absolute configuration of
one of these diarylmethylamines could be established by
single-crystal X-ray analysis. Further studies on the mecha-
nism are underway in our laboratory.
Synthesis of (1R,2S)-N,N,NЈ,NЈ-Tetramethyl-1-phenylpropane-1,2-
diamine (7c): The procedure was the same as described previously
for 7a, starting from (–)-(1R,2S)-N-methylephedrine. The product
was isolated in 85% yield as a white solid of [α]2D0 = –1.5 (c = 0.95,
CHCl3) after recrystallization in diethylether. Spectral data were in
agreement with the literature.[24]
Experimental Section
General Procedure for the Asymmetric Addition of Phenyllithium to
Imines: A solution of imine (0.5 mmol) in dry toluene (9 mL) was
added to a stirred solution of ligand (0.1 mmol or 1.5 mmol) in dry
toluene (1 mL) at room temperature. After cooling the medium to
–78 °C, phenyllithium (0.8 mL as a 1.9 m solution in cyclohexane/
Et2O, 70:30) was slowly added under argon. The resulting mixture
was stirred at –78 °C for 2 or 4 h (see Tables) and then quenched
at low temperature with methanol and water. Layers separated and
the aqueous layer was extracted three times with Et2O and once
with EtOAc. The combined organic phases were dried over K2CO3,
filtered and finally concentrated under reduced pressure. The re-
sulting residue was analyzed by 1H NMR spectroscopy to deter-
mine the conversion of the reaction by integration of the residual
peak of the aldimino proton. Then, it was purified by silica gel
column chromatography to give the desired product in the ee indi-
cated in tables. Spectral data were in agreement with the corre-
sponding racemic mixture synthesized independently.
General Techniques: Diethyl ether and toluene were dried over Na/
benzophenone and CaH2, respectively, and then distilled under ni-
trogen. TMEDA was distilled prior to use and stored under argon.
Other commercially available reagents were used without further
purification, unless otherwise indicated. Imines 2,[9] 5,[15] 8,[9] 9a,[16]
9b,[17] 9c,[18] 9d,[19] 9e,[20] 9f, 10,[21] and 11,[22] were generated by
condensation of p-anisidine with the corresponding aldehyde. Li-
gands 1b–f,[8] 7a,[12] 7c[12] and 7b[13] were synthesized as described
in the literature. nBuLi was purchased as a 1.6 m solution in hex-
anes and PhLi as a 1.9 m solution in cyclohexane/Et2O, 70:30. All
reactions were carried out under inert argon and in oven-dried
glassware. Temperatures indicated in the text refer to the inner reac-
tion mixtures. Flash column chromatography was performed using
silica gel 32–63 μm, 60 Å and thin layer chromatography on silica
gel plates. A 254 nm UV light and an ethanolic solution of ninhyd-
rine are used as developing agents. 1H NMR and 13C NMR spectra
were recorded at room temperature at 400 and 100 MHz, respec-
tively. Chemical shift values are expressed in ppm relative to resid-
ual CHCl3 calibrated to 7.26 for 1H NMR spectroscopy and the
CDCl3 signal is calibrated to 77.0 for 13C NMR spectroscopy. En-
antiomeric excesses were determined by Supercritical Fluid
Chromatography (capillary column, 10 psi H2), using racemic mix-
tures as references. Temperature programs are described as follows:
initial temperature (°C); initial time (min); temperature gradient
(°C·min–1); final temperature (°C). Circular dichroism spectra were
recorded in acetonitrile as solvent. The measurements were carried
out in the far-UV region.
General Procedure for the Asymmetric Addition of 2-Furyllithium,
2-Thienyllithium, 1-Naphthyllithium, 2-Naphthyllithium, 4-Chloro-
phenyllithium and 4-Methoxyphenyllithium to Imines: n-Butyllith-
ium (0.6 mL as a 1.6 m solution in hexanes, 1 mmol) was slowly
added under argon to a stirred solution of ligand (0.1 mmol or
1.0 mmol) and the appropriate aromatic compound (1.1 mmol) in
dry toluene (10 mL) cooled to –60 °C. The resulting mixture was
stirred at –60 °C for 1 h, during which time the metal–halogen ex-
change occurred. Then, the temperature of the medium was ad-
justed to the one indicated in the tables and a solution of imine
(0.5 mmol) in toluene (10 mL) was added carefully, so that the tem-
perature of the medium was only raised minimally. The reaction
mixture was stirred for the time indicated in the text. Quenching
and workup were the same as described previously for the addition
of phenyllithium, as well as the determination of conversions. Flash
silica gel column chromatography afforded the pure enantio-
enriched compounds, whose spectroscopic data were in agreement
with the corresponding racemic mixture synthesized independently.
Synthesis of (R,R)-(–)-N,N,NЈ,NЈ-Tetramethyl-trans-1,2-cyclohex-
anediamine (1a): (R,R)-1,2-Diammoniumcyclohexane mono-(+)-
tartrate[10] (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 refluxed for 2 h. After cooling to
room temperature, and then to 0 °C, the reaction mixture was made
basic until pH 12 with solid sodium hydroxide and extracted thor-
oughly with diethyl ether. The combined organic layers were dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by distillation in a bulb-to-bulb apparatus
(b.p. 50 °C/0.1 Torr) to afford a colorless liquid (11.35 g, 74%) of
[α]2D0 = –62.9 (c = 1.05, CHCl3). Spectral data were in agreement
with the literature.[23]
4-Methoxy-N-[phenyl(thiophen-2-yl)methyl]benzenamine (6a): Puri-
fication by silica gel chromatography (toluene) gave (–)-6a as a yel-
low oil of [α]2D5 = –13.1 (c = 1.03, CHCl3 for ee = 58% with 7b);
ee was determined by SFC: Chiralcel OJ, 200 bar, 2 mL·min–1, 25%
MeOH in CO2 (25%, 10 min), 30 °C, t1 = 7.7 min, t2 = 8.6 min. 1H
NMR: δ = 7.50–7.45 (m, 2 H), 7.39 (t, J = 7.3 Hz, 2 H), 7.35–7.29
(m, 1 H), 7.25 (dd, J = 5.0, 1.3 Hz, 1 H), 6.99–6.96 (m, 1 H), 6.94–
6.91 (m, 1 H), 6.76 (d, J = 8.8 Hz, 2 H), 6.60 (d, J = 8.8 Hz, 2 H),
5.72 (s, 1 H), 4.35–4.05 (br. s, 1 H), 3.74 (s, 3 H) ppm. 13C NMR:
δ = 152.5, 148.0, 142.8, 141.1, 128.8, 127.7, 127.1, 126.9, 125.0,
124.9, 115.0, 114.8, 59.6, 55.7 ppm. IR (neat): 3392, 3062, 1601,
1508, 1452, 1231, 1035, 819, 761, 698 cm–1. MS (EI), m/z (%): 295
(M, 10), 174, 173 (100), 129 (10). HRMS calcd. for C18H17NOS
295.1031, found 295.1027.
Synthesis of (1S,2S)-N,N,NЈ,NЈ-Tetramethyl-1-phenylpropane-1,2-
diamine (7a): Following the procedure of Dieter,[12] mesyl chloride
(5.59 mL, 72.0 mmol) was added dropwise under inert conditions
to a solution of (+)-(1S,2S)-N-methylpseudoephedrine (5.42 g,
30.0 mmol) and triethylamine (12.5 mL, 90.0 mmol) in diethylether
(180 mL) at 0 °C. A white precipitate appeared and after 30 min
triethylamine (16.7 mL, 120 mmol) was added once again and the
temperature was raised to room temperature. Dimethylamine
(96 mL, 5.6 m in EtOH) was added and the solution was stirred
vigorously overnight. The solution was made basic with aqueous
NaOH and organic layer was extracted with diethyl ether, washed
with 5% aq. NaHCO3 and water. The residue was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
N-[(Furan-2-yl)(phenyl)methyl]-4-methoxybenzenamine (6b): Purifi-
cation by silica gel chromatography (toluene) gave (+)-6b as a yel-
low oil of [α]2D5 = +5.9 (c = 0.50, CHCl3 for ee = 28% with 1a); ee
was determined by SFC: Chiralcel AD-H, 200 bar, 2 mL·min–1, 5%
Eur. J. Org. Chem. 2005, 4835–4842
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4839

A. Alexakis et al.
FULL PAPER
MeOH in CO2 (5%, 5 min, 1%·min–1, 20%, 5 min), 30 °C, t1
=
147.1, 142.5, 141.2, 129.5 (q, JC,F = 32.6 Hz), 129.0, 127.8, 127.6,
2
1
1
6.2 min, t2 = 7.7 min. H NMR: δ = 7.51–7.47 (m, 2 H), 7.45–7.39
(m, 3 H), 7.38–7.34 (m, 1 H), 6.80 (d, J = 9.1 Hz, 2 H), 6.63 (d, J
= 8.8 Hz, 2 H), 6.77 (dd, J = 3.2, 1.9 Hz, 1 H), 6.18 (br d, J =
3.3 Hz, 1 H), 5.59 (s, 1 H), 4.40–4.00 (br. s, 1 H), 3.76 (s, 3 H) ppm.
127.5, 125.7 (q, 3JC,F = 3.9 Hz), 124.2 (q, JC,F = 272.0 Hz), 114.8,
63.6, 55.7 ppm. IR (neat): 3397, 3030, 1618, 1509, 1416, 1322, 1242,
1109, 1065, 1035, 817, 740, 700 cm–1. MS (EI), m/z (%): 358 (M +
H, 16), 357 (M, 67), 250 (15), 236 (18), 235 (87), 215 (9), 173 (10),
13C NMR: δ = 155.4, 152.3, 142.0, 141.0, 140.6, 128.6, 127.6, 127.2, 166 (17), 165 (32), 145 (9), 123 (11), 122 (100), 105 (26), 95 (10),
114.8, 114.6, 110.2, 107.3, 57.6, 55.5 ppm. IR (neat): 3401, 2929,
1511, 1453, 1235, 1036, 819, 737, 699 cm–1. MS (EI), m/z (%): 279
(M, 11), 172 (12), 158 (14), 157 (100), 128 (22), 127 (10), 105 (14),
95 (10), 77 (14). HRMS calcd. for C18H17NO2 279.1259, found
279.1239.
77 (13). HRMS calcd. for C21H18F3NO 357.1340, found 357.1358.
N-[(Benzo[d][1,3]dioxol-6-yl)(phenyl)methyl]-4-methoxybenzenamine
(12e): Purification by silica gel chromatography (toluene) gave (–)-
12e as a yellow oil of [α]2D5–1.7 (c = 0.99, CHCl3 for ee = 64% with
1a); ee was determined by SFC: Chiralcel OD-H, 175 bar,
1.8 mL·min–1, 5% MeOH in CO2 (5%, 5 min, 1%·min–1, 20%),
N-[(4-Chlorophenyl)(phenyl)methyl]-4-methoxybenzenamine (12a):
Purification by silica gel chromatography (toluene) gave 12a as a
yellow oil of [α]2D5 = –13.6 [c = 0.97, CHCl3 for ee = 59% with
(–)-sparteine], +12.3 (c = 0.38, CHCl3 for ee = 64% with 1a); ee
was determined by SFC: Chiralpak AS-H, 200 bar, 2 mL·min–1,
1
30 °C, t1 = 15.8 min, t2 = 16.2 min. H NMR: δ = 7.30–7.22 (m, 3
H), 7.19 (br. s, 2 H), 6.90–6.72 (m, 2 H), 6.70–6.58 (m, 3 H), 6.43
(d, J = 8.8 Hz, 2 H), 5.85 (s, 2 H), 5.25 (s, 1 H), 3.90 (br. s, 1 H),
3.64 (s, 3 H) ppm. 13C NMR: δ = 152.2, 147.9, 146.7, 143.3, 141.6,
137.3, 128.7, 127.3, 127.2, 120.5, 114.7, 114.6, 108.3, 107.8, 101.0,
63.6, 55.7 ppm. IR (neat): 3397, 3027, 1610, 1509, 1231, 1035, 931,
818, 761, 700 cm–1. MS (EI), m/z (%): 333 (M, 11), 331 (19), 255
(37), 254 (11), 240 (35), 226 (63), 212 (15), 211 (70), 153 (12), 152
(15), 150 (10), 149 (100), 121 (11), 105 (31), 77 (53), 63 (14), 51
(13). HRMS calcd. for C21H19NO3 333.1365, found 333.1379.
25% MeOH in CO2 (25%, 15 min), 30 °C, t1 = 3.3 min, t2
=
3.7 min. 1H NMR: δ = 7.24–7.16 (m, 9 H), 6.70–6.58 (m, 2 H),
6.47–6.32 (m, 2 H), 5.30 (s, 1 H), 3.88 (br. s, 1 H), 3.63 (s, 3 H)
ppm. 13C NMR: δ = 152.4, 142.8, 141.6, 141.4, 133.0, 128.9, 128.7,
127.6, 127.5, 114.8, 114.7, 63.3, 55.8 ppm. IR (neat): 3402, 3028,
1602, 1509, 1452, 1241, 1035, 819, 750, 700 cm–1. MS (EI), m/z (%):
324 (M + H, 14), 323 (M, 64), 321 (82), 292 (M, 4), 244 (21), 216
(53), 201 (93), 165 (47), 139 (84), 111 (40), 105 (100), 77 (94), 51
(35). HRMS calcd. for C20H1835ClNO 323.1077, found 323.1059
and for C20H1837ClNO 325.1047, found 325.1071.
4-Methoxy-N-[(naphthalen-2-yl)(phenyl)methyl]benzenamine (13):
Purification by silica gel chromatography (toluene) gave (–)-13 as a
yellow oil of [α]2D5 = –1.6 (c = 1.01, CHCl3 for ee = 64% with 1a);
ee was determined by SFC: Chiralcel OD-H, 200 bar, 2 mL·min–1,
25 % MeOH in CO2 (25 %, 15 min), 30 °C, t1 = 10.4 min, t2
=
4-Methoxy-N-[(4-methoxyphenyl)(phenyl)methyl]benzenamine (12b):
Purification by silica gel chromatography (pentane/Et2O: 8:1.5)
gave (–)-12b as a yellow oil of [α]2D5 = –23.2 (c = 0.77, CHCl3 for
ee = 69% with 1a); ee was determined by SFC: Chiralcel OJ,
200 bar, 2 mL·min–1, 2% MeOH in CO2 (2%, 15 min), 30 °C, t1 =
11.5 min. 1HNMR (400 MHz, CDCl3): δ = 7.85–7.72 (m, 3 H),
7.50–7.20 (m, 9 H), 6.71 (d, J = 8.8 Hz, 2 H), 6.57 (d, J = 8.8 Hz,
2 H), 5.58 (s, 1 H), 3.71 (s, 3 H), 1.55 (br. s, 1 H) ppm. 13CNMR
(100 MHz, CDCl3): δ = 134.5, 133.4, 132.8, 130.1, 129.5, 129.1,
128.8, 128.5, 128.0, 127.6, 127.4, 126.1, 125.9, 125.8, 125.6, 114.7,
55.7 ppm. MS (EI), m/z (%) 339 (M, 18), 218 (15), 217 (100), 216
(11), 215 (21), 212 (11), 202 (23). HRMS calcd. for C24H21NO
339.1623, found 339.1646.
1
11.3 min, t2 = 13.2 min. H NMR: δ = 7.29–7.16 (m, 7 H), 6.80–
6.75 (m, 2 H), 6.65–6.61 (m, 2 H), 6.42 (d, J = 8.0 Hz, 2 H), 5.29
(s, 1 H), 3.88 (br. s, 1 H), 3.70 (s, 3 H), 3.63 (s, 3 H) ppm. 13C
NMR: δ = 158.8, 152.1, 143.4, 141.8, 135.5, 128.7, 128.6, 127.3,
127.2, 114.7, 114.1, 63.2, 55.8, 55.3 ppm. IR (neat): 3398, 3000,
1610, 1509, 1452, 1243, 1034, 819, 761, 700 cm–1. MS (EI), m/z (%):
319 (M, 10), 197 (100), 165 (9), 153 (9). HRMS calcd. for
C21H21NO2 319.1572, found 319.1580.
4-Methoxy-N-[(naphthalen-1-yl)(phenyl)methyl]benzenamine[22] (14):
Purification by silica gel chromatography (pentane/Et2O, 10:1) gave
14 as a colorless oil of [α]2D5 = –40.7 (c = 3.57, CHCl3 for ee = 90%
with 1a), + 60.1 (c = 0.32, CHCl3 for ee = 94% with 7a); ee was
determined by SFC: Chiralcel OD-H, 175 bar, 1.8 mL·min–1, 20%
MeOH in CO2 (20%, 15 min), 30 °C, t1 = 9.6 min, t2 = 12.2 min.
4-Methoxy-N-[phenyl(p-tolyl)methyl]benzenamine (12c): Purifica-
tion by silica gel chromatography (pentane/Et2O, 10:1) gave (–)-12c
as a yellow oil of [α]2D5 = –17.3 (c = 0.96, CHCl3 for ee = 63% with
1a); ee was determined by SFC: Chiralcel OD-H, 200 bar,
2 mL·min–1, 2% MeOH in CO2 (2%, 5 min, 1%·min–1, 15%),
4-Methoxy-N-[(naphthalen-1-yl)(o-tolyl)methyl]benzenamine (15):
Purification by silica gel chromatography (toluene) gave 15 as a
white solid. M.p. 86–87 °C (pentane/diethyl ether). [α]2D5 = –22.3 (c
= 0.18, CHCl3 for ee = 86% with 1a), +36.6 (c = 0.40, CHCl3 for
ee = 94% with 7a); ee was determined by SFC: Chiralcel OJ, 170
bar, 2 mL·min–1, 10% MeOH in CO2 (10%, 5 min, 2%·min–1, 25%,
5 min), 30 °C, t1 = 10.0 min, t2 = 10.9 min. 1H NMR (400 MHz,
CDCl3): δ = 7.95–7.75 (m, 4 H), 7.55–7.10 (m, 7 H), 6.73 (d, J =
8.8 Hz, 2 H), 6.49 (d, J = 7.4 Hz, 2 H), 6.25 (s, 1 H), 3.73 (s, 3 H),
2.31 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 136.4, 134.3,
131.6, 131.0, 129.1, 128.4, 127.8, 127.6, 126.7, 126.5, 125.8, 125.8,
125.7, 123.6, 115.0, 55.9, 19.4 ppm. IR (neat): 3400, 2928, 1750,
1510, 1242, 1038, 819, 791, 758 cm–1. MS (EI), m/z (%): 353 (29),
232 (22), 231 (100), 216 (28), 215 (30). HRMS: ESI (positive) calcd.
for [M – H]+ C25H22NO 352.1701, found 352.1713.
1
30 °C, t1 = 13.0 min, t2 = 13.5 min. H NMR: δ = 7.30–7.15 (m, 7
H), 7.04 (d, J = 7.8 Hz, 2 H), 6.63 (d, J = 8.8 Hz, 2 H), 6.42 (d, J
= 9.0 Hz, 2 H), 5.30 (s, 1 H), 3.90 (br. s, 1 H), 3.63 (s, 3 H), 2.24
(s, 3 H) ppm. 13C NMR: δ = 152.1, 143.3, 141.7, 140.3, 136.9,
129.4, 128.7, 127.3, 127.2, 114.7, 63.6, 55.7, 21.1 ppm. IR (neat):
3403, 3026, 1602, 1509, 1452, 1242, 1037, 819, 732, 700 cm–1. MS
(EI), m/z (%): 304 (M + H, 5), 303 (M, 26), 182 (14), 181 (100),
166 (20), 165 (18), 152 (6), 77 (5). HRMS calcd. for C21H21NO
303.1623, found 303.1602.
4-Methoxy-N-{[4-(trifluoromethyl)phenyl](phenyl)methyl}benzen-
amine (12d): Purification by silica gel chromatography (pentane/
Et2O, 10:1) gave (+)-12d as a yellow oil of [α]2D5 = +33.7 (c = 1.01,
CHCl3 for ee = 60% with 1a); ee was determined by SFC: Chi-
N-[(4-Chlorophenyl)(naphthalen-1-yl)methyl]-4-methoxybenzen-
ralpak AS-H, 200 bar, 2 mL·min–1, 5% MeOH in CO2 (5%, 6 min, amine (16): Purification by silica gel chromatography (pentane/
2%·min–1, 15%), 30 °C, t1 = 3.0 min, t2 = 4.0 min. H NMR: δ = Et2O, 20:1) gave (–)-16 as a colorless oil of [α]2D5 = –36.9 (c = 0.38,
1
7.48 (d, J = 8.4 Hz, 2 H), 7.42 (d, J = 8.4 Hz, 2 H) 7.24–7.12 (m,
5 H), 6.63 (d, J = 9.1 Hz, 2 H), 6.39 (d, J = 8.8 Hz, 2 H), 5.36 (s,
1 H), 3.91 (br. s, 1 H), 3.61 (s, 3 H) ppm. 13C NMR: δ = 152.5,
CHCl3 for ee = 90% with 1a); ee was determined by SFC: Chiralcel
OJ, 170 bar, 2 mL·min–1, 10 % MeOH in CO2 (10 %, 5 min,
1
2%·min–1, 25%, 10 min), 30 °C, t1 = 23.0 min, t2 = 24.7 min. H
4840
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4835–4842

Asymmetric Addition of Aryllithium Reagents to Imines
FULL PAPER
J. Med. Chem. 2005, 48, 1169–1178. For some reviews: h) D.
Enders, U. Reinhold, Tetrahedron: Asymmetry 1997, 8, 1895–
1946; i) R. Bloch, Chem. Rev. 1998, 98, 1407–1438; j) T.
Le Gall, C. Mioskowski, D. Lucet, Angew. Chem. Int. Ed. 1998,
37, 2580–2627; k) S. Kobayashi, H. Ishitani, Chem. Rev. 1999,
99, 1069–1094; l) J. A. Ellman, T. D. Owens, T. P. Tang, Acc.
Chem. Res. 2002, 35, 984–995.
a) H. Fujihara, K. Nagai, K. Tomioka, J. Am. Chem. Soc.
2000, 122, 12055–12056; b) J. R. Porter, J. F. Traverse, A. H.
Hoveyda, M. L. Snapper, J. Am. Chem. Soc. 2001, 123, 984–
985; c) J. R. Porter, J. F. Traverse, A. H. Hoveyda, M. L. Snap-
per, J. Am. Chem. Soc. 2001, 123, 10409–10410; d) S. Dahmen,
S. Bräse, J. Am. Chem. Soc. 2002, 124, 5940–5941; e) A. Boezio,
A. B. Charette, J. Am. Chem. Soc. 2003, 125, 1692–1693; f)
L. C. Akullian, M. L. Snapper, A. H. Hoveyda, Angew. Chem.
Int. Ed. 2003, 42, 4244–4247; g) H.-L. Zhang, H. Liu, X. Cui,
A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong, Synlett 2005, 615–618.
Concerning cetirizine, see: a) D. A. Pflum, H. S. Wilkinson,
G. J. Tanoury, D. W. Kessler, H. B. Kraus, C. H. Senanayake,
S. A. Wald, Org. Process Res. Dev. 2001, 5, 110–115; b) D. A.
Pflum, D. Krishnamurthy, Z. Han, S. A. Wald, C. H. Sen-
anayake, Tetrahedron Lett. 2002, 43, 923–926; concerning
SNC-80, see: c) N. Plobeck, D. Delorme, Z.-Y. Wei, H. Yang,
F. Zhou, P. Schwarz, L. Gawell, H. Gagnon, B. Pelcman, R.
Schmidt, S.-Y. Yue, C. Walpole, W. Brown, E. Zhou, M. Lab-
arre, K. Payza, S. St-Onge, A. Kamassah, P.-E. Morin, D. Pro-
jean, J. Ducharme, E. Roberts, J. Med. Chem. 2000, 43, 3878–
3894; d) Z.-Y. Wei, W. Brown, B. Takasaki, N. Plobeck, D.
Delorme, F. Zhou, H. Yang, P. Jones, L. Gawell, H. Gagnon,
R. Schmidt, S.-Y. Yue, C. Walpole, K. Payza, S. St-Onge, M.
Labarre, C. Godbout, A. Jakob, J. Butterworth, A. Kamassah,
P.-E. Morin, D. Projean, J. Ducharme, E. Roberts, J. Med.
Chem. 2000, 43, 3895–3905.
K. Tomioka, I. Inoue, M. Shindo, K. Koga, Tetrahedron Lett.
1990, 31, 6681–6684.
N. Hermanns, S. Dahmen, C. Bolm, S. Bräse, Angew. Chem.
Int. Ed. 2002, 41, 3692–3694.
a) T. Hayashi, M. Ishigedani, J. Am. Chem. Soc. 2000, 122,
976–977; b) N. Tokunaga, Y. Otomaru, K. Okamoto, K. Uey-
ama, R. Shintani, T. Hayashi, J. Am. Chem. Soc. 2004, 126,
13584–13585; c) Y. Otomaru, N. Tokunaga, R. Shintani, T.
Hayashi, Org. Lett. 2005, 7, 307–310. For the addition of aryl-
boroxines to N-tosylarylimines see also: d) M. Kuriyama, T.
Soeta, X. Hao, Q. Chen, K. Tomioka, J. Am. Chem. Soc. 2004,
126, 8128–8129. For addition of arylboronic acids to diphenyl-
phosphinoylimines: e) D. J. Weix, Y. Shi, J. A. Ellman, J. Am.
Chem. Soc. 2005, 127, 1092–1093.
NMR: δ = 8.04 (d, J = 7.3 Hz, 1 H), 7.94 (d, J = 7.6 Hz, 1 H),
7.84 (d, J = 7.8 Hz, 1 H), 7.55–7.22 (m, 8 H), 6.76 (d, J = 8.6 Hz,
2 H), 6.53 (d, J = 8.1 Hz, 2 H), 6.16 (s. 1 H), 4.07 (br. s, 1 H), 3.76
(s, 3 H) ppm. 13C NMR: δ = 152.3, 141.4, 141.0, 137.6, 134.1,
133.2, 131.1, 129.4, 129.0, 128.9, 128.4, 126.6, 125.8, 125.7, 125.5,
123.4, 114.9, 114.3, 59.5, 55.7 ppm. IR (neat): 3403, 3051, 1597,
1508, 1240, 1014, 781, 735, 699 cm–1. MS (EI), m/z (%): 374 (11),
373 (46), 372 (34), 371 (63), 370 (55), 260 (20), 253 (34), 252 (18),
251 (100), 249 (14), 217 (14), 216 (70), 215 (73), 127 (14), 92 (15),
77 (24), 64 (10). HRMS calcd. for C24H2035ClNO 373.1233, found
373.1234.
[2]
4-Methoxy-N-[(naphthalen-1-yl)(p-tolyl)methyl]benzenamine (17):
Purification by silica gel chromatography (toluene) gave 17 as a
yellow oil of [α]2D5 = –86.6 (c = 0.30, CHCl3 for ee = 88% with 1a),
+47.9 (c = 0.14, CHCl3 for ee = 92% with 7a); ee was determined
by SFC: Chiralcel OJ, 170 bar, 2 mL·min–1, 10% MeOH in CO2
[3]
(10%, 5 min, 2%·min–1, 25%, 10 min), 30 °C, t1 = 14.5 min, t2
=
16.0 min. 1H NMR: δ = 7.96 (d, J = 7.1 Hz, 1 H), 7.80 (d, J =
7.1 Hz, 1 H), 7.70 (d, J = 8.3 Hz, 1 H), 7.48–7.30 (m, 4 H), 7.28–
7.20 (m, 3 H), 7.12–7.03 (m, 1 H), 6.63 (d, J = 6.8 Hz, 2 H), 6.40
(d, J = 8.8 Hz, 2 H), 6.04 (s, 1 H), 3.97 (br. s, 1 H), 3.62 (s, 3 H),
2.25 (s, 3 H) ppm. 13C NMR: δ = 152.0, 141.7, 139.5, 137.9, 137.1,
134.1, 131.1, 129.4, 128.9, 128.0, 126.3, 125.5, 125.3, 123.6, 114.8,
114.2, 59.8, 55.7, 21.1 ppm. IR (neat): 3400, 3000, 1510, 1242, 1030,
800, 785 cm–1. MS (EI), m/z (%): 353 (M, 18), 232 (26), 231 (100),
230 (22), 229 (17), 217 (11), 216 (33), 215 (44), 123 (17), 108 (24),
80 (8). HRMS calcd. for C25H23NO 353.1780, found 353.1773.
N-{[Benzo[d][1,3]dioxol-6-yl](naphthalen-1-yl)methyl}-4-methoxy-
benzenamine (18): Purification by silica gel chromatography (tolu-
ene) gave 18 as a yellow oil of [α]2D5 = –59.1 (c = 0.80, CHCl3 for
ee = 86% with 1a), +35.0 (c = 0.85, CHCl3 for ee = 90% with 7a);
ee was determined by SFC: Chiralcel OD-H, 170 bar, 2 mL·min–1,
[4]
[5]
[6]
20% MeOH in CO2 (20%, 30 min), 30 °C, t1 = 15.3 min, t2
=
18.1 min. 1H NMR: δ = 8.10–8.00 (m, 1 H), 8.00–7.75 (m, 2 H),
7.58–7.40 (m, 5 H), 6.98–6.85 (m, 2 H), 6.80–6.67 (m, 3 H), 6.53
(d, J = 8.6 Hz, 1 H), 6.07 (s, 1 H), 6.00–5.90 (m, 2 H), 3.72 (s, 3
H), 1.55 (br. s, 1 H) ppm. 13C NMR: δ = 148.2, 147.1, 134.3, 131.3,
129.1, 128.4, 126.6, 125.8, 125.7, 125.6, 123.7, 121.6, 115.0, 108.7,
108.6, 101.3, 55.9 ppm. IR (neat): 3400, 3000, 1750, 1511, 1237,
1038, 800 cm–1. MS (EI), m/z (%): 383 (M, 12), 373 (46), 262 (25),
261 (100), 231 (29), 203 (34), 202 (32), 201 (8), 77 (4), 65 (4).
HRMS calcd. for C25H21NO3 383.1521, found 383.1516.
[7]
For the asymmetric addition of organolithium compounds to
imines, see for example: a) I. Inoue, M. Shindo, K. Koga, K.
Tomioka, Tetrahedron: Asymmetry 1993, 4, 1603–1606; b) S. E.
Denmark, N. Nakajimka, O. Nicaise, J. Am. Chem. Soc. 1994,
116, 8797–8798; c) S. E. Denmark, N. Nakajimka, O. Nicaise,
A.-M. Faucher, J. Org. Chem. 1995, 60, 4884–4892; d) C. A.
Jones, I. G. Jones, M. North, C. R. Pool, Tetrahedron Lett.
1995, 36, 7885–7888; e) S. E. Denmark, O. Nicaise, Chem.
Commun. 1996, 999–1004; f) P. G. Andersson, F. Johansson, D.
Tanner, Tetrahedron 1998, 54, 11549–11566; g) M. Hasegawaa,
D. Taniyama, K. Tomioka, Tetrahedron 2000, 56, 10153–10158;
h) S. Arrasate, E. Lete, N. Sotomayor, Tetrahedron: Asymmetry
2001, 12, 2077–2082. For the addition of methyllithium to
imines related to the synthesis of the alkaloid salsolidine, see:
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Acknowledgments
The authors wish to thank PPG-SIPSY for financial support, and
Du Pont de Nemours GmbH for a generous gift of cyclohexane
diamine.
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FULL PAPER
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Received: June 20, 2005
Published Online: September 29, 2005
4842
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4835–4842