Enantioselective nucleophilic addition of organometallic reagents to quinoline: Regio-, stereo- and enantioselectivity

Article abstract of DOI:10.1016/j.tet.2004.06.088

Some 2-alkyl-1,2-dihydroquinoline and some 2-aryl-1,2-dihydroquinoline were obtained by enantioselective addition of methyl-, butyl-, phenyl- and 1-naphthyllithium on quinoline. Bisoxazolines were used as external chiral ligands, giving enantiomeric exces

Full text of DOI:10.1016/j.tet.2004.06.088

Tetrahedron 60 (2004) 8221–8231
Enantioselective nucleophilic addition of organometallic reagents
to quinoline: regio-, stereo- and enantioselectivity
*
Franck Amiot, Laure Cointeaux, Emmanuelle Jan Silve and Alexandre Alexakis
Department of Organic Chemistry, University of Geneva, 30, Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
Received 31 March 2004; revised 9 June 2004; accepted 16 June 2004
Available online 8 July 2004
Abstract—Some 2-alkyl-1,2-dihydroquinoline and some 2-aryl-1,2-dihydroquinoline were obtained by enantioselective addition of methyl-,
butyl-, phenyl- and 1-naphthyllithium on quinoline. Bisoxazolines were used as external chiral ligands, giving enantiomeric excess up to
79%. The ligand could be used in catalytic amounts without significant loss of enantioselectivity.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
presence of (2)-sparteine.9 Even a catalytic amount of
ligand could be used. We have shown that a direct addition
of butyllithium on isoquinoline gave a chiral 1,2-dihydroi-
soquinoline with an enantiomeric excess of 57% (Scheme
1).
The nucleophilic 1,2 addition of organometallic reagents on
imines and related compounds is a well-known method to
synthesise amines. The asymmetric version has extensively
been studied, both with stoichiometric covalent auxiliaries1
and with external chiral ligands, in stoichiometric or
catalytic amounts.2 In the particular case of azaaromatic
compounds, the nucleophilic addition is more difficult
because of the already poor reactivity of the CvN double
bond and the aromatic nature of these systems.3 Even fewer
examples concern quinoline.
Quinoline derivatives are compounds of biological interest4
and nucleophilic addition of an organometallic reagent,
such as organolithiums and Grignards, is a good method to
obtain a racemic 1,2- or 1,4-dihydroquinoline.5 The use of
quinolinium salts, to enhance the reactivity, often improves
the results.6 Nevertheless, not much is known about the
synthesis of non-racemic alkylated 1,2-dihydroquinolines.
Diastereoselective4d,5h and an enantioselective synthesis are
known, using chiral aminals as auxiliary.7 Excellent
enantiomeric excess could be obtained with phenyl and
naphthyl Grignard. To our knowledge, only the cyanation of
the quinoline has been reported with catalytic amounts of
chiral ligand to give the corresponding dihydroquinoline
with 80% ee.8 The enantioselective addition of organo-
metallic reagents, as carbon nucleophiles, does not seem to
have been explored with quinoline.
Scheme 1. Enantioselective addition of butyllithium to isoquinoline.
The regioselectivity of this nucleophilic addition was
complete at the benzylic position 1, but stabilisation of the
adduct with methylchloroformate gave a mixture of
N-acylated product 2 and bisacylated product 3. The ratio
of these two products was invariably 70/30 when tempera-
ture, solvent and amount of reagents were changed. Within
the framework of our study on heteroaromatic compounds,
we are now interested in enlarging the method previously
described with isoquinoline, to quinoline as aromatic imine.
In our earlier work, we reported the first enantioselective
addition of organolithium reagents on isoquinoline in the
2. Results and discussion
Keywords: 1,2-Dihydroquinoline; Enantioselective addition; Chiral ligand;
Organolithium reagents; Organometallics; Bioxazoline.
The regioselectivity of the nucleophilic addition was studied
with methyllithium, a relatively less reactive organolithium
*
Corresponding author. Tel.: þ41-22-379-65-22; fax: þ41-22-379-32-15;
e-mail address: alexadre.alexakis@chiorg.unig.ch
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.088

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F. Amiot et al. / Tetrahedron 60 (2004) 8221–8231
Table 1. Regioselectivity of the addition of methyllithium to quinoline
Entries
Solvent
T [8C]
Time (min)
Ligand
Ratio 5/6 or 8
Yield or conversion [%]
1
2
3
4
5
6
Toluene
Toluene
Toluene
Et2O
Et2O
Et2O
220
220
220
240
220
220
60
60
60
10
10
10
—
DME (0.5 equiv)
TMEDA (0.5 equiv)
—
—
DME (0.5 equiv)
100/0
100/0
100/0
100
100
100
65a
100a
100a
0b
18b
81b
a
Conversion estimated of crude NMR spectra.
Yield of isolated product.
b
reagent. Table 1 shows that only the 1,2 addition was
observed, giving the 2-methyl-1,2-dihydroquinoline 5 in
65% conversion after 1 h. No re-aromatised product 7 was
observed in the crude mixture and the final dihydroquinoline
5 was stable enough to be studied by crude NMR analysis.
However, this product could hardly be purified by flash
chromatography on silicagel without a large part of re-
aromatisation.
good yield without any by-product. Even more importantly,
with asymmetric catalysis in view, the nucleophile can be
activated by sub-stoichiometric amounts of an external
ligand like DME or TMEDA in toluene or in Et2O. These
results had comforted us in the possibility of an enantio-
selective activation of this nucleophilic addition.
The rate of the reaction was also studied with methyl
Grignard as carbon nucleophile (Table 2). In the absence of
methyl chloroformate, no reaction took place. Therefore, an
activation of quinoline, as its quinolinium salt is needed.
When dimethoxyethane (DME) was used as a non-chiral
ligand (entry 2), the conversion was complete under the
same conditions, indicating that the presence of a 1,2 diether
enhanced the rate of the reaction. No change in the
regioselectivity was observed and only the 1,2 adduct 5
was obtained. A similar behaviour was observed with a
diamine, such as tetramethylethylenediamine (TMEDA)
(entry 3).
Table 2. Regioselectivity of the addition of methyl Grignard to the
quinoline
Using the method previously explored with isoquinoline,
the lithiated intermediate 4 was trapped, in Et2O, with
methylchloroformate after 10 min (Table 1). In this case,
only the N-acylation was observed. The regioselectivity was
not affected and the 1,2-dihydroquinoline 8 was the unique
product. The influence of the temperature was determined
and we can see that at 240 8C no reaction was observed
after 10 min (entry 4). This also shows that methylchloro-
formate did not activate the imine moiety6a in the
nucleophilic addition but only stabilises the adduct. When
the temperature rose to 220 8C, the 1,2-dihydroquinoline 8
could be obtained in 18% yield (entry 5). However, the
presence of sub-stoichiometric amounts of DME increased
dramatically the yield up to 81% (entry 6).
Entries
Solvent
T [8C]
Ligand
Yield [%]
8/9
1
2
3
4
5
6
7
Et2O
Et2O
THF
Toluene
Toluene
CH2Cl2
CH2Cl2
220
220
220
220
220
220
220
—
DME 0.5 equiv
41
16
28
59
34
94
60
100/0
100/0
100/0
100/0
100/0
100/0
100/0
—
—
DME 0.5 equiv
—
DME 0.5 equiv
At 220 8C, methylchloroformate was added 10 min after
the nucleophile in order to observe a significant rate of
reaction. In Et2O, without any ligand, the isolated yield of
dihydroquinoline 8 was 41% (entry 1). Only the 1,2
adduct was observed. With 0.5 equiv. of dimethoxyethane,
the isolated yield was only 16% (entry 2) but the
These results show that the nucleophilic addition of an
alkyllithium reagent on quinoline is completely regio-
selective and the 1,2-dihydroquinoline can be isolated in

F. Amiot et al. / Tetrahedron 60 (2004) 8221–8231
8223
regioselectivity was complete. In tetrahydrofuran, the yield
2.1. Enantioselective additions with chiral diether 10
was worse than in Et2O with 28% of isolated product (entry
3). In toluene, dihydroquinoline 8 was obtained in 59%
yield (entry 4) but the presence of 0.5 equiv of dimethoxy-
ethane decreased the yield down to 34% (entry 5). The best
result was obtained in dichloromethane (entry 6) with 94%
yield of the 1,2 adduct. Thus, in striking contrast to
organolithium reagents, dimethoxyethane had a detrimental
effect, the dihydroquinoline being obtained in only 60%
yield. In all these experiments, the regioselectivity was
complete at position 2 and no trace of 1,4 adduct 9 was
observed. Unfortunately, the presence of a bidentate ligand
such DME, dramatically decreased the yield of
dihydroquinoline.
In summary, we can say that with organometallics such as
alkyl Grignard, dimethylzinc and trimethylaluminum,
quinoline has to be activated as a quinolinium salt. In all
these cases, the yields were not as good as with
organolithium reagents, which is able to add directly on
the imine moiety. The presence of a diether decreased the
yield, and the regioselectivity in the case of dimethylzinc.
For these reasons, alkyllithium reagents appeared to us to be
the best candidates for the 1,2 enantioselective nucleophilic
addition to quinoline. So far, they were tested in the
presence of three different ligands: the chiral 1,2 diether
10,10 developed by Tomioka, (2)-sparteine11 11 as a 1,2
diamine, and the bisoxazolines 12a, 12b and 12c (Fig. 1).
This regioselective 1,2 addition was also observed with
trimethylaluminum (Scheme 2).
Scheme 2. Regioselectivity of the addition of AlMe3 to quinoline.
Trimethylaluminum did not react after 12 h at room
temperature. This nucleophile was not reactive enough
with quinoline and activation as iminium salt with
methylchloroformate was again required. In this case, the
1,2-dihydroquinoline 8 could be obtained in 31% yield at
260 8C. The regioselectivity was determined by NMR
analysis of the crude and only the 1,2 adduct could be
observed.
Figure 1. (R,R)-Dimethoxydiphenylethane 10, (2)-sparteine 11,
bisoxazolines 12a, 12b and 12c.
Firstly, methyllithium was used in the presence of 1 equiv of
the chiral diether 10 (Table 4, entry 1). The desired
dihydroquinoline was obtained in 67% isolated yield but the
enantiomeric excess, determined by chiral GC analysis, was
only 20%.
As for trimethylaluminum, dimethylzinc did not react with
quinoline and methylchloroformate was used as an
activating agent (Table 3).
The catalytic version of this addition was tested with the
more reactive n-butyllithium. Table 4 shows that conversion
to the 2-butyl-1,2-dihydroquinoline 13 was good at low
temperature in Et2O or in toluene (entries 2–4). Unfortu-
nately, the enantiomeric excess was very low. Phenyl-
lithium (entries 5–9), as well as 1-naphthyllithium (entries
10 and 11), also showed very low enantioselectivity.
However, it is striking to observe that, despite the very
low yield, a moderate ee of 26% (although the best in this
series!) could be obtained in toluene (entry 6). The yields
were usually better with catalytic amount of ligand,
indicating that the ligand might be destroyed by RLi, thus
consuming most of this nucleophile.
Table 3. Regioselectivity of the addition of dimethylzinc to quinoline
Entries
Solvent
T [8C]
Ligand
Yield [%]
8/9
2.2. Enantioselective additions with (2)-sparteine 11
1
2
3
THF
Et2O
Et2O
220
220
220
—
—
30
18
16
75/25
.90/10
55/45
DME 0.5 equiv
The 1,2 diether 10 being rather inefficient, we have
attempted to enhance the chiral induction by changing the
nature of the chelating heteroatoms. (2)-Sparteine 11,
already known to be a good complexing chiral ligand for
organolithium reagents,11 appeared to us to be a good
alternative. Using the same procedure as before, the
organolithium reagent was firstly added to the mixture of
(2)-sparteine 11 and quinoline 1 (Table 5).
Methylchloroformate was added 10 min after the dimethyl-
zinc. In tetrahydrofuran at 220 8C, a modest yield of 30%
was observed and the ratio 8/9, determined by NMR
analysis, was found to be 75/25 (entry 1). In Et2O, under the
same conditions, the regioselectivity was better (entry 2) but
the yield of isolated product was only 18%. The presence of
a diether in the solution did not increase the yield and
decreased dramatically the regioselectivity. In this case the
ratio of 1,2- and 1,4-dihydroquinoline was 55/45 (entry 3).
In toluene at 240 8C, butyllithium gave the desired
dihydroquinoline 13 with 15% ee in the presence of

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F. Amiot et al. / Tetrahedron 60 (2004) 8221–8231
Table 4. Enantioselective addition of organolithium reagent to quinoline in the presence of (R,R)-dimethoxydiphenylethane 10
Entries
Solvent
R
T [8C]
Ligand [equiv]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
Et2O
Et2O
Toluene
Toluene
Et2O
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Me
Bu
Bu
Bu
220 1 h
260 1 h
260 1 h
278 1 h
278 2 h
278 2 h
278 2 h
260 2 h
260 2 h
250 2 h
250 2 h
1
0.2
0.2
0.2
1
1
0.2
1
67a
86a
68a
53a
16
7
54
20
74
57
45
20
4
0
4
Phb
,2
26
,2
12
,2
,4
5
Phb
Phb
Phb
9
10
11
Phb
0.2
1
0.2
Naphthb
Naphthb
a
Conversion determined by crude NMR analysis.
PhLi and NaphthLi were prepared by halogen–metal exchange between PhI or NaphthI and n-BuLi.
b
Table 5. Enantioselective addition of butyllithium and methyllithium to quinoline in the presence of (2)-sparteine
Entries
Solvent
R
T [8C]
(2)-Sparteine [equiv]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8a
9a
10
Toluene
Toluene
Toluene
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Me
240 1 h
240 1 h
280 1 h
240 1 h
240 1 h
260 1 h
280 1 h
240 1 h
260 1 h
220 1 h
0.2
1
1
1
0.2
1
1
1
1
1
67
98
86
98
100
99
86
100
76
69
15
18
19
16
13
18
16
10
12
5
a
By precomplexing the butyllithium and (2)-sparteine.
0.2 equiv of ligand (entry 1). Increasing the amount of
ligand up to 1 equiv under the same conditions allowed to
improve the yield up to 98% of isolated product, but the
enantiomeric excess was only 18% (entry 2). This result
could not be enhanced by cooling the temperature to 280 8C
and enantiomeric excess was still 19% (entry 3). Using Et2O
instead of toluene gave lower enantiomeric excess with
1 equiv (entry 4), or 0.2 equiv of ligand (entry 5), even at
lower temperatures (entries 6 and 7). Compared to diether
10, (2)-sparteine 11 gave both higher yields and ee’s.
Finally, methyllithium was tested with stoichiometric
amounts of ligand (entry 10). Both yield and enantiomeric
excess of the dihydroquinoline 8 were comparable than
before, with diphenyldimethoxyethane 10 as ligand.
to optimise the chiral induction by pre-complexing the
ligand and the organolithium reagent before the reaction
with quinoline. The precomplexation was done by stirring
n-BuLi and (2)-sparteine at room temperature, for 30 min,
then cooling this complex at the desired reaction tempera-
ture. Table 5 shows that 1 equiv of (2)-sparteine gave the
dihydroquinoline 13 with 10% ee at 240 8C (entry 8), which
was lower than without any pre-complexation (entry 4). At
260 8C, an enantiomeric excess of 12% could be observed
(entry 9).
The same precomplexation procedure was repeated in
toluene. However, we observed, this time, the nucleophilic
addition of benzyl lithium, rather than of n-BuLi.
Compared to isoquinoline, (2)-sparteine gave disappoint-
ingly low results with quinoline. So far, we have attempted
This organolithium reagent was formed by deprotonation of
the solvent, toluene, in the presence of a diamine, such as

F. Amiot et al. / Tetrahedron 60 (2004) 8221–8231
8225
Table 6. Nucleophilic addition of benzyl lithium to quinoline by deprotonation of toluene in the presence of ligand
Entries
T [8C]
Ligand
Yield [%]
16a/16ba
ee [%] 16a/16b
1
2
260 1 h
260 1 h
11 (1 equiv)
TMCDA (1 equiv)
62
80
83/17
79/21
44/0
26/3
a
Determined by NMR analysis.
(2)-sparteine 11. In addition, the reaction was not
regioselective and two products, the 2-benzyl-1,2-dihydro-
quinoline 16a and the 4-benzyl-1,2-dihydroquinoline 16b,
were isolated, in a 83/17 ratio. The enantiomeric excess of
the 1,2 adduct, 16a, was 44%, while the 1,4 adduct, 16b,
was racemic (Table 6, e0ntry 1). Similar results were
obtained with (R,R) N,N -tetramethyl cyclohexane-1,2-
diamine (TMCDA) (entry 2), but with a lower enantio-
selectivity. Attempts were also made in the presence of
diether 10 or bisoxazoline 12a; toluene was not deproto-
nated by n-BuLi, a result which is consistent with the
previous observations made in the presence of TMEDA or
DABCO.12 However, no nucleophilic addition at all was
observed on quinoline, indicating that n-BuLi was con-
sumed on reaction with diether 10 or bisoxazoline 12a, at
room temperature.
260 8C after 2 h (entry 5). When 2 equiv of ligand were
added, the yield was stable and a slightly lower ee was
obtained (entry 3). By increasing the temperature to
260 8C, an enantiomeric excess of 63% could be described
(entry 4). Under the same conditions, whenever ether was
used instead of toluene, the ee and the yield were similar
(entries 5, 7 and 8). Therefore, with 1 equiv of sparteine, the
enantiomeric excess was still up to 66%. In presence of
0.2 equiv of ligand, at 278 8C after 1 h, we found that the
ee decreased dramatically. In toluene (entry 2), that value
was 7% and rose up to 24% in ether (entry 6). In all
cases, the enantiomeric excess was the best result observed
thus far.
To extend this result, we also tested the addition of
1-naphthyllithium. The first observation was that the yield
was satisfactory, but the enantiomeric excess was worse. In
stoichiometric conditions, we have observed that in toluene
at 278 8C (entry 9) or 250 8C (entry 11), the ee was the
same with about 17%. Using Et2O instead of toluene (entry
13), under the same conditions the enantiomeric excess
increased to 28% and the yield was also better with 86%.
Under catalytic conditions, in toluene (entries 10 and 12) or
in ether (entry 14), the desired product 15 was obtained with
a chiral induction, but the ee decreased, as before with
phenyllitium.
Phenyllithium generally affords better enantioselecttivities
with (2)-sparteine than with other ligands.13 The addition
of phenyllithium to quinoline in stoichiometric amount of
sparteine gave the 1,2-dihydroquinoline 14 in 82% yield and
with 66% ee (Table 7, entry 1). These values were obtained
in toluene at 278 8C after 1 h (entry 1), as well as in ether at
Table 7. Enantioseletive addition of aryllithium to quinoline in the
presence of (2)-sparteine
2.3. Enantioselective additions with bisoxazolines 12a,
12b and 12c
The reactions with (2)-sparteine and alkyllithiums being a
rather unselective, we have attempted to increase the
enantiomeric excess of the 1,2-dihydroquinolines 8 and
13, using more efficient ligands. Bisoxazolines were known
to afford good results in enantioselective addition to acyclic
imines.13a We therefore synthesised and tested bisoxazoline
12a derived from L-valinol.
Entries
Solvent
R
T [8C]
Ligand
[equiv]
Yield
[%]
ee
[%]
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Et2O
Et2O
Et2O
Et2O
Toluene
Toluene
Toluene
Toluene
Et2O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
278 1 h
278 1 h
278 1 h
260 2 h
278 1 h
278 1 h
260 2 h
220 2 h
278 2 h
278 2 h
250 2 h
250 2 h
278 2 h
278 2 h
1
0.2
2
1
1
0.2
1
1
1
0.2
1
82
38
88
91
55
60
82
70
69
24
37
66
86
64
66
7
57
63
67
24
66
57
17
9
16
6
28
12
We have first tested the enantioselective addition with the
bisoxazoline 12a using methyllithium as carbon nucleophile
(Table 8). The best result was obtained in toluene at 240 8C
with one equiv of chiral ligand. An enantiomeric excess of
63% could be observed (entry 1). Catalytic amounts of this
bisoxazoline under the same conditions gave the dihydro-
quinoline 8 in 43% isolated yield with an enantiomeric
excess of 30% (entry 2). Decreasing the temperature to
260 8C did not allow a better enantiomeric excess (entry 3).
Using Et2O instead of toluene (entry 4) gave similar results
in term of enantioselectivity. Nevertheless, bisoxazoline
9
Naphth
Naphth
Naphth
Naphth
Naphth
Naphth
10
11
12
13
14
0.2
1
0.2
Et2O
RLi was prepared by halogen–metal exchange between RI and n-BuLi.

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Table 8. Enantioselective addition of alkyllithium to quinoline in the
presence of bisoxazoline 12a
chiral ligand, associated to the organolithium reagent, was
trapped by the lithiated amide intermediate produced by the
nucleophilic addition, as indicated in Scheme 3.
The chiral ligand would then become inefficient for another
catalytic cycle and the enantioselectivity would decrease
during the reaction. In order to verify this hypothesis, the
reaction was reproduced in toluene at 240 8C in the
presence of catalytic amount of chiral bisoxazoline 12a.
Methylchloroformate was added after 15, 30, 45, or 75 min
and in each reaction, the enantiomeric excess was compared
to the conversion (Table 8). At 15 min, an enantiomeric
excess of 62% was observed for a conversion of 30% (entry
5). This enantiomeric excess is higher than those observed
in catalytic version, and it is closer to the stoichiometric
version (entry 1). After 30 min, the conversion rose up to
42% but the enantiomeric excess decreased to 57% (entry
6). We observed that the reaction was slower than in the first
15 min, indicating that the acceleration of the reaction, due
to the ligand, was not so well pronounced. After 75 min
(entry 8), the decrease of the enantiomeric excess down to
54% was significant enough to be taken into consideration,
and the conversion was only 54%. In regard to these two
results: decrease of the enantiomeric excess and slow down
the reaction rate, it appeared clear to us that the catalyst
loses its efficiency during the reaction and this tends to
prove the trapping of the ligand by the lithiated
intermediate.
Entries
Solvent
R
T [8C]
Ligand
[equiv]
Yied
[%]
ee
[%]a
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Et2O
Me
Me
Me
Me
Me
Me
Me
Me
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
240 2 h
240 1 h
260 2 h
260 2 h
240 15 min
240 30 min
240 45 min
240 75 min
260 1 h
270 1 h
260 1 h
270 1 h
280 1 h
260 1 h
270 1 h
280 1 h
1
47
43
40
63
30
32
31
62
57
59
54
72
79
66
67
67
42
45
39
0.2
0.2
0.2
0.2
0.2
0.2
0.2
1
31
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Et2O
30b
42b
44b
54b
63
9
10
11
12
13
14
15
16
1
85
75
63
55
90
79
87
0.2
0.2
0.2
0.2
0.2
0.2
Et2O
Et2O
a
Determined by chiral GC.
Conversion determined by crude NMR analysis.
b
12a appeared to be the best chiral ligand for this reaction
and we wanted to check what were the limitations of such an
enantioselective nucleophilic addition in the presence of an
external chiral ligand. Particularly, we wanted to know if the
With butyllithium and a stoichiometric amount of ligand
12a we obtained the 1,2-dihydroquinoline 13 in 63%
isolated yield with 72% ee at 260 8C in toluene (Table 8,
entry 9). By decreasing the temperature to 270 8C, an
enantiomeric excess of 79% could be observed (entry 10).
When catalytic amounts (0.2 equiv) of ligand were used
under the same conditions, the enantiomeric excess was still
up to 66% (entry 11). In this case, decreasing the
temperature to 270 8C (entry 12) or 280 8C (entry 13)
did not allow a better enantioselectivity, but rather
decreased the yield of the reaction. Changing the solvent
to Et2O gave better yields but lower enantiomeric excess
(entries 14–16). Thus, toluene appeared to be the best
solvent in this reaction.
Scheme 3. Trapping of the chiral ligand by the lithiated intermediate.
Table 9. Enantioselective addition of phenyl- and naphthyllithium to quinoline in the presence of bisoxazoline 12a
Entries
Solvent
Ra
Ph
Ph
Ph
Ph
Ph
Naphth
Naphth
Naphth
Naphth
T [8C]
Ligand [equiv]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
Toluene
Toluene
Toluene
Et2O
278 1 h 00 min
278 1 h 30 min
255 1 h 30 min
278 1 h 30 min
255 1 h 30 min
270 2 h
250 2 h
278 2 h
250 2 h
1
6
,4
0
,4
0
0
8
0
0
0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
28
57
63
82
20
55
36
65
Et2O
Toluene
Toluene
Et2O
Et2O
a
RLi was prepared by halogen–metal exchange between RI and n-BuLi.

F. Amiot et al. / Tetrahedron 60 (2004) 8221–8231
8227
It was expected that phenyllithium would not behave
favourably with bisoxazoline ligands.13 This is indeed the
case (Table 9).
Table 11. Enantioselective addition of alkyllithium to quinoline in the
presence of bisoxazoline 12c
Table 9, shows that only a trace amount of compounds 14,
with low ee, was obtained when the addition of phenyl-
lithium to quinoline was carried out in toluene, at 278 8C
and with 1 equiv of ligand (entry 1). Catalytic amounts of
bisoxazoline 12a gave the 2-phenyl- and 2-naphthyl-
dihydroquinoline 14 and 15 with a better yield. The yields
were better in ether than in toluene, but only racemates were
obtained. Furthermore, the temperature influenced this
value. In the case of the addition of phenyllithium, in
toluene the yield was 28% at 278 8C (entry 2) and was
enhanced to 57% at 255 8C (entry 3). In ether, the values
were, respectively 63 and 82% (entries 4 and 5). Never-
theless, the increase of temperature did not change the
enantiomeric excess.
Entries Solvent
R
T [8C] Ligand [equiv] Yied [%] ee [%]a
1
2
3
4
5
6
Toluene Me 240 1 h
Et2O Me 240 2 h
Toluene Bu 270 2 h
Toluene Bu 270 2 h
Toluene Bu 240 2 h
0.2
0.2
1
69
86
57
79
89
96
21
22
69
41
40
20
0.2
0.2
0.2
Et2O
Bu 270 2 h
a
Determined by chiral GC.
with a benzyl group, gave a lower enantiomeric excess than
the bisoxazoline 12a, but a better than ligand 12b.
Nevertheless, catalytic amount of ligand can be used with
a small loss of enantioselectivity (entries 4 and 5). Again, in
ether, the ee are considerably lower than in toluene (entry
6). With ligand 12c, methyllithium reacts normally,
affording an ee of 21–22%, both in ether and toluene.
Thus, bisoxazoline 12c has an intermediate behaviour,
compared to 12a and 12b. In view of the insignificant
enantioselectivity observed with phenyllithium and
bisoxazoline 12a, no attempts were made with the other
bisoxazolines.
So far, bisoxazoline 12a gave an enantiomeric excess of
79% with n-BuLi, and the chiral induction with MeLi
allowed an enantiomeric excess of around 63% in
stoichiometric version or at the beginning of the catalytic
reaction. The limitation of such a catalytic reaction is the
trapping of the chiral ligand by the amine produced during
the reaction. Bisoxazoline 12b, having a tertiobutyl instead
of an isopropyl group, is usually a better enantiodiscrimi-
nating ligand, due to the increased steric interactions. We
therefore prepared and tested this new ligand (Table 10).
Table 10. Enantioselective addition of alkyllithium to quinoline in the
presence of bisoxazoline 12b
2.4. Determination of the absolute configuration
In order to determine the absolute configuration of the
addition products, 1,2-dihydroquinolines 13 and 14 were
converted to the known tetrahydroquinolines 19 and 20.14
Thus, 13 and 14 were hydrogenated with palladium on
charcoal to afford tetrahydroquinolines 17 and 18, in 98 and
81% yield respectively (Scheme 4).
Entries Solvent
R
T [8C] Ligand [equiv] Yied [%] ee [%]a
1
2
3
4
5
Toluene Me 240 2 h
Toluene Bu 270 1 h
Toluene Bu 270 1 h
Toluene Bu 240 1 h
0.2
1
0.2
0.2
0.2
,5
80
70
69
80
nd
32
37
7
Et2O
Bu 270 1 h
8
a
Determined by chiral GC.
Scheme 4. Hydrogenation of 1,2-dihydroquinolines 13 and 14.
Methyllithium and catalytic amount of ligand 12b, in
toluene, did not afford significant addition product (entry 1).
With the more reactive butyllithium, an enantiomeric excess
of 37% was measured, with a good isolated yield (entry 3).
Increasing the amount of ligand 12b to 1 equiv, improved
the yield to 80% but lowered the ee to 32%. Increasing the
temperature or using ether instead of toluene, dramatically
reduced the enantioselectivity (entries 4 and 5).
Then, the carbamate functionality was removed by a
Bouveault reaction with alkyllithium to provide the known
products14 19 and 20 with the same enantiomeric excess as
the starting 1,2-dihydroquinolines 13 and 14 and with a
moderate non-optimised yield (31–35%) (Scheme 5).
In a last attempt to optimise these results, we have used the
benzylbisoxazoline 12c, thinking that p-staking interactions
with the substrate would have a favourable role.
With butyllithium as nucleophile, Table 11 shows that an
enantiomeric excess of 69% could be obtained with 1 equiv
of this ligand (entry 3), indicating that the bisoxazoline 12c,
Scheme 5. Removal of the carbamate of 1,2,3,4-tetrahydroquinolines 19
and 20.

8228
F. Amiot et al. / Tetrahedron 60 (2004) 8221–8231
The specific rotation of 2-butyl-1,2,3,4-tetrahydroquinoline
19 gave a negative value of 239 for an enantiomeric excess
of 41%, showing, by comparison with the literature data,14
that the nucleophilic addition of n-butyllithium on quino-
line, with bisoxazoline 12c as ligand, gave (S)-2-butyl-1,2-
dihydroquinoline 13. For 2-phenyl-1,2,3,4-tetrahydroquino-
line 20, the sign of the specific rotation was negative with
231.4 for an enantiomeric excess of 64.6%. Thus,
according to the literature data,14 the nucleophilic addition
of phenyllithium on quinoline, with sparteine as ligand,
gave (R)-2-phenyl-1,2-dihydroquinolines 14.
Gemini-200 at 50 MHz and Brucker DRX-400 at 100 MHz
in CDCl3, standard CDCl3 (77.0 ppm). Infra-red spectra
(IR): FT-IR Perkin–Elmer 1600. The high-resolution mass
spectra (HRMS) were recorded in the EI (70 eV) mode.
4.1.1. 2-Methyl-1,2-dihydroquinoline (5). To a stirred
solution of quinoline (0.3 mL; 2.5 mmol) in dry toluene
(10 mL) was added DME (1.3 mL; 1.25 mmol) under an
argon atmosphere at 220 8C. Then methyllithium (3.1 mL;
5 mmol) was added. After 1 h, the solution was hydrolysed
with water, extracted with Et2O (3£20 mL), dried with
MgSO4, and filtered. The solvent was evaporated. The crude
product was purified by flash chromatography on silicagel
with cyclohexane/Et2O (80/20) and the dihydroquinoline 5
was obtained in 57% yield as yellow oil. 1H NMR (CDCl3,
200 MHz): d 7.0–6.35 (m, 4H); 6.30 (m, 1H); 5.50 (m, 1H);
4.42 (m, 1H); 3.70 (s, 1H); 1.30 (d, 3H). 13C NMR (CDCl3,
50 MHz): d 144.4; 129; 127.6; 127.2; 125.6; 120.9; 117.9;
113.1; 48.8; 24.7. IR: 3388; 3033; 2963; 1639; 1602; 1487;
3. Conclusion
In conclusion, we have shown that it was possible to
synthesise alkyl and aryl 1,2-dihydroquinolines from quino-
line by direct addition of organometallic reagents. This
reaction was completely regioselective with organolithium
reagents, methyl Grignard and trimethylaluminum, and only
the 1,2 addition was observed. Dimethylzinc gave a mixture
of 1,2 and 1,4 adduct, depending on the experimental
conditions. Organolithium reagents could react without any
activation of the imine moiety. By this way, the N-acylation
of the lithiated intermediate did not induced any by-product
and allowed very good yields. With alkyllithium reagents, in
the presence of a chiral ligand, an enantiomeric excess up to
79% could be obtained with butyllithium, using the
bisoxazoline 12a as an external ligand. The catalytic
version gave lower enantiomeric excess due to the trapping
of the ligand, but optimisation of these results will be done,
using more efficient chiral ligands. With aryllithium
reagents, (2)-sparteine 11 gave enantiomeric excess up to
66%, in stoichiometric conditions. So, in this case, the
diamines as external ligands appeared to be good candidates
to optimise this reaction.
1453; 1318; 1277; 1122; 1038 cm21
.
4.1.2. 2-Methyl-1,2-dihydro-[N-methoxycarbonyl]-
quinoline (8). With MeMgBr. To a stirred solution of
freshly distilled quinoline (0.3 mL, 2.5 mmol) in dry
dichloromethane (20 mL) was added methylmagnesium
bromide (1 mL, 3 mmol as a 3 M solution in Et2O) at
220 8C under an argon atmosphere. After 10 min at
220 8C, methylchloroformate (2.2 mL, 3 mmol) was
added dropwise. After 15 min, the solution was hydrolysed
with a solution of NH4Cl, extracted with dichloromethane
(3£20 mL), dried with MgSO4, filtered and evaporated. The
crude product was purified by flash chromatography with
cyclohexane/Et2O (90/10) as eluent and the desired 1,2-
dihydroquinoline 8 was obtained in 94% yield.
With Me2Zn. To a stirred solution of freshly distilled
quinoline (0.3 mL, 2.5 mmol) in dry tetrahydrofuran
(10 mL) was added Me2Zn (1.2 mL, 3 mmol as a 2 M
solution in toluene) at 220 8C under an argon atmosphere.
After 10 min, methylchloroformate (2.2 mL, 3 mmol) was
added dropwise. After 15 min, the solution was hydrolysed
with a solution of NH4Cl, extracted with Et2O (3£20 mL),
dried with MgSO4, filtered and evaporated. The crude
product was purified by flash chromatography on silicagel
using cyclohexane/Et2O (95/5) as eluent. A mixture of
inseparable 1,2-dihydroquinoline 8 and 1,4-dihydroquino-
line 9 was obtained in 30% yield.
4. Experimental
4.1. General remarks
All the reactions were carried out under argon atmosphere
with magnetic stirring, unless otherwise specified. Two
necked flasks were used with an internal thermometer.
Solvents were dried by distillation from a drying agent as
follow: Et2O (Na/benzophenone), THF (Na/benzophenone),
toluene (CaH2), CH2Cl2 (CaH2). Commercial MeLi Fluka in
THF/Cumene 1/1, commercial n-BuLi Fluka in hexane,
were used. Flash chromatography column: SiO2
With Me3Al. To a stirred solution of freshly distilled
quinoline (0.3 mL, 2.5 mmol) Et2O was added Me3Al
(2 mL, 4 mmol as a 2 M solution in toluene) under an
argon atmosphere at 220 8C. Methylchloroformate
(2.2 mL, 3 mmol) was then added dropwise. After 1 h
30 min at 220 8C, the solution was hydrolysed with water,
extracted with Et2O (3£20 mL), dried with MgSO4, filtered
and evaporated. The crude product was purified by flash
chromatography on silicagel using cyclohexane/Et2O
(95/5). The 1,2-dihydroquinoline 8 was obtained in 31%
yield.
˚
(Brunschwig 32–63, 60 A). Gas chromatography: Hewlett
Packard 5790A, integrator HP 3390A, HP-1 Capillary
column, 10psi H2. Chiral GC: Hewlett Packard, Lipodex E
column 200034-32. Programs are written as follow: Initial
temperature (8C)-initial time (min)-increasing temperature
(8C/min)-final temperature (8C)-final time (min). Super-
critical Fluid Chromatography (SFC): Berger, Column
Chiralcel OJ and OD-H. Melting Point: Kofler hot stage.
[a]2D0: Perkin–Elmer 241 polarimeter. 1H NMR: Varian
Gemini-200 at 200 MHz and Brucker DRX-400 at 400 MHz
in CDCl3, standard CDCl3 (7.27 ppm). Coupling constants
are expressed in Hz (multiplicity: singlet ‘s’, doublet ‘d’,
triplet ‘t’, quadruplet ‘q’, multiplet ‘m’). 13C NMR: Varian
4.1.3. (S)22-Methyl-1,2-dihydro-[N-methoxycarbonyl]-
quinoline (8). To a stirred solution of freshly distilled
quinoline (0.3 mL, 2.5 mmol) and bisoxazoline 12a

F. Amiot et al. / Tetrahedron 60 (2004) 8221–8231
8229
(747 mg, 0.5 mmol) in dry toluene (20 mL) was added
methyllithium (3 mL, 3 mmol as a 1 M solution in THF/
cumene 1/1) at 260 8C. After 2 h methylchloroformate
(0.23 mL, 3 mmol) was added. After 10 min, the solution
was hydrolysed with a solution of NH4Cl, extracted with
Et2O (2£20 mL) and dichloromethane (2£20 mL), dried
with MgSO4 and filtered. The crude solution was purified by
flash chromatography on silicagel with cyclohexane/Et2O
(80/20) as eluent and the dihydroquinoline 8 was obtained in
47% yield as pale pink oil. The enantiomeric excess was
found to be 63% by chiral GC. TLC: Rf¼0.42 using
NH4Cl, extracted with ether (2£20 mL) and dichloro-
methane (2£20 mL). The organic layers were dried over
MgSO4, filtered and evaporated. The crude oil was purified
by chromatography on silica gel with cyclohexane/ether
(85/15) as eluent, and the product 14 was obtained in 82%
yield as yellow oil. An enantiomeric excess of 66% was
determined by chiral SFC analysis, using the column
chiralcel OD-H. TLC: Rf¼0.30 using cyclohexane/Et2O
(9/1). 1H NMR (CDCl3, 400 MHz): d 7.63 (s br, 1H); 7.43–
7.37 (m, 2H); 7.37–7.24 (m, 4H); 7.21 (dd, 1H, J1¼7.6 Hz,
J2¼1.8 Hz); 7.15 (t, 1H, J¼7.3 Hz); 6.74 (m, 1H); 6.35–
6.24 (m, 2H); 3.92 (s, 3H). 13C NMR (CDCl3, 100 MHz): d
155.3; 139.7; 134.7; 128.6; 128.3; 127.9; 127.2; 127.1;
126.4; 125.4; 124.7; 124.4; 55.7; 53.3. IR: 2953, 1694;
1488; 1436; 1377; 1324; 1270; 1125; 1028; 844; 760;
695 cm21. MS-EI: m/z (relative intensity) 265 (41); 188
(100); 144 (66); 129 (19); 102 (11); 77 (17); 59 (15).
HRMS: calcd for C17H15NO2 (Mþz) 265.1103. Found:
265.1087. Program of chiral SFC: OD-H 6%-6-1-15%;
elute: MeOH; pressure: 200 Bar; flow rate: 2 mL/min;
30 8C. [a]2D5¼2438.2 (c¼3.1 in CHCl3) for an ee of 66%.
1
cyclohexane/Et2O (9/1). H NMR (CDCl3, 200 MHz): d
7.6–7.0 (m, 4H); 6.4 (d, 1H, J¼9.5 Hz); 6.0 (dd, 1H,
J1¼5.9 Hz, J2¼9.7 Hz); 5.10 (q, 1H, J¼6.3 Hz); 3.79 (s,
3H); 1.10 (d, 3H, J¼6.7 Hz). 13C NMR (CDCl3, 50 MHz): d
155.1; 134; 130; 131.1; 127.8; 127.4; 124.9; 126.6; 124.6.
IR: 2955; 1710; 1491; 1439; 1316; 1129; 765 cm21. MS-EI:
m/z (relative intensity) 203 (19); 188 (100); 144 (89); 129
(18); 115 (10); 102 (9); 77 (11); 59 (15). Anal. calcd for
C12H13NO2 (203.24): C, 70.92; H, 6.45; N, 6.89. Found: C,
69.46; H, 6.63; N, 6.52. Program of GC analysis: 90-1-170.
[a]2D0¼þ22.9 (c¼1.2 in CHCl3) for an ee of 63%.
4.1.6. (R)-2-Naphthyl-1,2-dihydro-[N-methoxycarbon
yl]-quinoline (15). To a solution of 1-iodonaphthalene
(1.8 mL, 1.2 mmol, 1.2 equiv) and (2)-sparteine (0.23 mL,
1 mmol, 1 equiv) in dry Et2O (3.5 mL) was added dropwise
n-BuLi (0.75 mL, 1.2 mmol, as a 1.6 M solution in hexane)
at 278 8C under an argon atmosphere. The solution was
stirred during 1 h at 278 8C, and was diluted with 3.5 mL of
Et2O. Then quinoline (0.12 mL, 1 mmol, 1 equiv) was
added, and the yellow reaction turned orange, with time.
After 2 h at 278 8C, methylchloroformate (0.09 mL,
1.2 mmol, 1.2 equiv) was added and the solution became
yellow. After 10 min, the solution was quenched with a
solution of NH4Cl, extracted with ether (2£7 mL) and
dichloromethane (2£7 mL). The organic layers were dried
over MgSO4, filtered and evaporated. The crude oil was
purified by chromatography on silica gel with cyclohexane/
ether (85/15) as eluent, and the product 15 was obtained in
85.6% yield as yellow oil. An enantiomeric excess of 27.5%
was determined by chiral SFC analysis, using the column
chiralcel OJ. TLC: Rf¼0.31 using cyclohexane/Et2O (9/1).
1H NMR (CDCl3, 400 MHz): d 8.63 (d, 1H, J¼7.8 Hz); 7.92
(d, 1H, J¼8.1 Hz); 7.79 (d, 1H, J¼8.1 Hz); 7.71 (t, 1H,
J¼7.7 Hz); 7.59 (t, 1H, J¼7.6 Hz); 7.40 (d, 1H, J¼7.1 Hz);
7.33–7.24 (m, 2H); 7.24–7.14 (m, 3H); 7.09 (d, 1H,
J¼5.8 Hz); 6.73 (d, 1H, J¼9.6 Hz); 6.38 (dd, 1H,
J1¼9.6 Hz, J2¼6.1 Hz); 3.87 (s, 3H). 13C NMR (CDCl3,
100 MHz): d 155.4; 135.3; 135.2; 134.1; 130.4; 129.0;
128.9; 128.6; 127.8; 127.3; 126.6; 126.3; 125.7; 125.4;
125.2; 124.8; 123.7; 52.9; 53.4. IR: 2953; 1697; 1489; 1437;
1300; 1265; 1123; 1040; 754 cm21. MS-EI: m/z (relative
intensity) 315 (51); 256 (62); 188 (100); 128 (17); 101 (5);
77 (9); 59 (10). HRMS: calcd for C21H17NO2 (Mþ.)
315.1259. Found: 315.1247. Program of chiral SFC: OJ
10%-2-1-25%; elute: MeOH; pressure: 200 Bar; flow rate:
2 mL/min; 30 8C. [a]2D5¼2169.5 (c¼1.305 in CHCl3) for an
ee of 27.5%.
4.1.4. (S)-2-Butyl-1,2-dihydro-[N-methoxycarbonyl]-
quinoline (13). To a solution of freshly distilled quinoline
(0.3 mL, 2.5 mmol) and bisoxazoline 12a (735 mg,
2.5 mmol) in dry toluene (20 mL) was added n-BuLi
(1.8 mL, 3 mmol as a 1.6 M solution in hexane) at 270 8C
under an argon atmosphere. After 1 h, methylchloroformate
(0.23 mL, 3 mmol) was added. After 10 min, the solution
was hydrolysed with a solution of NH4Cl, extracted with
Et2O (2£20 mL) and dichloromethane (2£20 mL), dried
over MgSO4, filtered and evaporated. The crude product
was purified by flash chromatography on silicagel with
cyclohexane/Et2O (80/20) as eluent and gave the 1,2-
dihydroquinoline 13 in 80% yield as yellow oil. The
enantiomeric excess of 79% was determined by chiral GC
analysis using the Lipodex E column. TLC: Rf¼0.50 using
1
cyclohexane/Et2O (9/1). H NMR (CDCl3, 200 MHz): d
7.23–7.08 (m, 4H); 6.46 (d, 1H, J¼8 Hz); 6.09 (m, 1H);
5.00 (m, 1H); 3.81 (s, 3H); 1.45–1.27 (m, 6H); 0.88 (m,
3H). 13C NMR (CDCl3, 50 MHz): d 154.9; 134.3; 130.1;
127.4; 127.1; 126; 124.7; 124.4; 124.2; 52.8; 32.5; 27.3;
22.3; 13.9. IR: 2931; 1699; 1490; 1438; 1325; 1250; 1131;
764 cm21. MS-EI: m/z (relative intensity) 245 (3); 188
(100); 144 (68); 129 (16); 102 (6); 77 (6); 59 (11). Anal.
calcd for C15H19NO2 (245.32): C, 73.44; H, 7.81; N, 5.71.
Found: C, 73.48; H, 7.89; N, 5.48. Program of chiral GC:
90-1-170-20. [a]2D0¼þ35.7 (c¼1.02 in CHCl3) for an ee of
79%.
4.1.5. (R)-2-Phenyl-1,2-dihydro-[N-methoxycarbonyl]-
quinoline (14). To a solution of iodobenzene (0.34 mL,
3 mmol, 1.2 equiv) and (2)-sparteine (0.57 mL, 2.5 mmol,
1 equiv) in dry toluene (10 mL) was added dropwise n-BuLi
(1.88 mL, 3 mmol, as a 1.6 M solution in hexane) at 278 8C
under an argon atmosphere. The solution was stirred during
1 h at 278 8C, and was diluted with 11 mL of toluene. Then
quinoline (0.29 mL, 2.5 mmol, 1 equiv) was added, and the
yellow reaction turned orange, with time. After 1 h at
4.1.7. 2-Benzyl-1,2-dihydro-[N-methoxycarbonyl]-
quinoline (16a) and 4-benzyl-1,2-dihydro-[N-methoxy
carbonyl]-quinoline (16b). To a solution of (2)-sparteine
(0.23 mL, 1 mmol, 1 equiv) in dry toluene (8 mL) was
278 8C,
methylchloroformate
(0.23 mL,
3 mmol,
1.2 equiv) was added and the solution became yellow.
After 10 min, the solution was quenched with a solution of

8230
F. Amiot et al. / Tetrahedron 60 (2004) 8221–8231
added n-BuLi (0.75 mL, 1.2 mmol as a 1.6 M in hexane) at
25 8C under an argon atmosphere. The solution was stirred
for 30 min. The temperature was then cooled to 260 8C and
quinoline (0.12 mL, 1 mmol) was added. After 1 h at
260 8C, methylchloroformate (0.09 mL, 1.2 mmol) was
added. After 10 min, the solution was hydrolysed with a
solution of NH4Cl, extracted with Et2O (2£10 mL) and
dichloromethane (2£10 mL). The organic layers were dried
with MgSO4, filtered and evaporated. The crude product
was purified by flash chromatography on silicagel with
cyclohexane/Et2O (95/5) as eluent and the products 16a and
16b were obtained in 62% global yield as yellow oil.
Enantiomerics excess of 44% for 16a and 0% for 16b were
determined by chiral SFC analysis, using the column
chiralcel OD-H.
hydrogenation was performed at room temperature under H2
(1 atm) for 3 h. The crude product was then filtered through
Celite and the solvent was evaporated. The crude oil was
purified by chromatography on silica gel with cyclohexane/
ether (85/15) as eluent, and the product 18 was obtained in
81% yield as yellow oil. TLC: Rf¼0.20 using cyclohexane/
1
Et2O (85/15). H NMR (CDCl3, 400 MHz): d 7.75 (d, 1H,
J¼7.8 Hz); 7.34–7.19 (m, 6H); 7.16–7.06 (m, 2H); 5.52 (t,
1H, J¼7.7 Hz); 3.74 (s, 3H); 2.75–2.61 (m, 2H); 2.57–2.48
(m, 1H); 1.98–1.87 (m, 1H). 13C NMR (CDCl3, 100 MHz):
d 155.5; 143.3; 137.6; 132.6; 128.3; 127.5; 126.7; 126.4;
125.9; 124.8; 124.0; 58.2; 52.8; 33.1; 26.0. IR: 2952; 1698;
1491; 1438; 1380; 1323; 1236; 1133; 1056; 908; 727;
647 cm21. MS-EI: m/z (relative intensity) 267 (100); 235
(15); 208 (68); 176 (20); 144 (6); 130 (24); 91 (45); 77 (25);
51 (9). Anal. calcd for C17H17NO2 (267.33): C, 76.38; H,
6.41; N, 5.24. Found: C, 75.32; H, 6.52; N, 4.96.
[a]2D5¼276.3 (c¼1.355 in CHCl3). The enantiomeric excess
was not determined.
Product 16a. 1H NMR (CDCl3, 200 MHz): d 7.71 (s br, 1H);
7.35–7.13 (m, 9H); 6.55 (d, 1H, J¼9.6 Hz); 6.00 (dd, 1H,
J1¼5.8 Hz, J2¼9.6 Hz); 5.27 (s br, 1H); 3.66 (s, 3H); 2.75
(dd, 1H, J1¼2.8 Hz, J2¼7.5 Hz). 13C NMR (CDCl3,
50 MHz): d 155.0; 138.9; 137.8; 131.4; 129.9; 129.0;
128.8; 128.7; 126.8; 125.7; 124.8; 121.9; 113.1; 54.6; 53.3;
40.7. Program of chiral SFC: OD-H 2%-2-1-20%; MeOH;
200 Bar; 2 mL/min; 30 8C. [a]2D0¼2162.3 (c¼1.1 in CHCl3)
for an ee of 44%.
4.1.10. (S)-2-Butyl-1,2,3,4-tetrahydroquinoline (19). To a
solution of 17 (125.2 mg, 0.51 mmol, 1 equiv) in dry ether
(5 mL) was added dropwise n-BuLi (1.25 mL, 2 mmol, as a
1.6 M solution in hexane) at 220 8C under an argon
atmosphere. The mixture was stirred and the temperature
was allowed to rise to room temperature. After 3 h, the
solution was quenched with methanol, and the solvents were
evaporated. The crude product was purified by chromato-
graphy on silica gel with cyclohexane/ether (98/2) as eluent,
and the product 19 was obtained in 31% yield as yellow oil.
An enantiomeric excess of 40.8% was determined by chiral
SFC analysis, using the column chiralcel AD. TLC:
Rf¼0.63 using cyclohexane/Et2O (85/15). 1H NMR
(CDCl3, 400 MHz): d 7.01–6.95 (m, 2H); 6.62 (t, 1H,
J¼7.6 Hz); 6.50 (d, 1H, J¼7.3 Hz); 3.85 (s br, 1H); 3.30–
3.20 (m, 1H); 2.88–2.69 (m, 2H); 2.03–1.93 (m, 1H);
1.67–1.55 (m, 1H); 1.55–1.47 (m, 2H); 1.46–1.33 (m, 4H);
0.95 (t, 1H, J¼7.1 Hz). 13C NMR (CDCl3, 100 MHz): d
144.6; 129.2; 126.7; 121.5; 117.0; 114.1; 51.6; 36.3; 28.1;
27.9; 26.4; 22.8; 14.1. IR: 2927; 1608; 1485; 1352; 1310;
1276; 1214; 745 cm21. MS-EI: m/z (relative intensity) 189
(17); 144 (2); 132 (100); 117 (8); 77 (5); 51 (1). Program of
chiral SFC: AD 5%-2-1-15%; elute: MeOH; pressure: 200
Bar; flow rate: 2 mL/min; 30 8C. [a]2D6¼238.7 (c¼0.54 in
CHCl3) for an ee of 40.8%. The absolute configuration was
assigned as (S) by analogy to the lit. data. (Lit.14
[a]2D5¼þ79.9 (c¼1 in CHCl3) for an ee of 92% for (R)
stereochemistry).
1
Product 16b. H NMR (CDCl3, 200 MHz): d 7.93 (d, 1H,
J¼8.4 Hz); 7.28–7.18 (m, 4H); 7.10 (t, 1H, J¼7.3 Hz);
7.04–6.93 (m, 4H); 5.28 (dd, 1H, J1¼5.8 Hz, J2¼7.6 Hz);
3.82 (s, 3H); 3.62 (q, 1H, J¼6.4 Hz); 2.85 (d, 2H,
J¼6.8 Hz). 13C NMR (CDCl3, 50 MHz): d 152.8; 138.4;
136.5; 130.8; 129.5; 128.3; 127.9; 126.5; 126.3; 126.0;
124.7; 121.3; 112.6; 53.1; 44.4; 40.1. Program of chiral
SFC: OD-H 2%-2-1-20%; elute: MeOH; pressure: 200 Bar;
flow rate: 2 mL/min; 30 8C.
4.1.8. (S)-2-Butyl-1,2,3,4-tetrahydro-[N-methoxy car-
bonyl]-quinoline (17). To a solution of 13 of 40.4% ee
(181.5 mg, 0.74 mmol, 1 equiv) in methanol (15 mL) was
added 2 mol% of palladium on activated charcoal. The
hydrogenation was performed at room temperature under H2
(1 atm) for 3 h. The crude product was then filtered through
Celite and the solvent was evaporated. The crude oil was
purified by chromatography on silica gel with cyclohexane/
ether (85/15) as eluent, and the product 17 was obtained in
98% yield as yellow oil. TLC: Rf¼0.23 using cyclohexane/
1
Et2O (85/15). H NMR (CDCl3, 400 MHz): d 7.50 (d, 1H,
J¼7.8 Hz); 7.21–7.14 (m, 1H); 7.13–7.08 (m, 1H); 7.04 (t,
1H, J¼7.3 Hz); 4.61–4.52 (m, 1H); 3.78 (s, 3H); 2.77–2.63
(m, 2H); 2.26–2.14 (m, 1H); 1.70–1.60 (m, 1H); 1.59–1.50
(m, 1H); 1.42–1.20 (m, 5H); 0.95–0.79 (m, 3H). 13C NMR
(CDCl3, 100 MHz): d 155.4; 136.6; 131.2; 127.9; 125.8;
125.5; 124.0; 52.8; 52.6; 32.3; 28.8; 28.0; 24.4; 22.4; 13.9.
IR: 2930; 1697; 1492; 1438; 1388; 1323; 1213; 1128; 1057;
911; 765; 716 cm21. MS-EI: m/z (relative intensity) 247
(19); 190 (100); 130 (14); 118 (16); 91 (7); 77 (6); 59 (7).
[a]2D5¼þ36.7 (c¼1.145 in CHCl3). The enantiomeric excess
was not determined.
4.1.11. (R)-2-Phenyl-1,2,3,4-tetrahydroquinoline (20). To
a solution of 18 (144.8 mg, 0.55 mmol, 1 equiv) in dry
toluene (4 mL) was added dropwise MeLi (2.2 mL,
2.2 mmol, as a 1 M solution in THF/cumene: 1/1) at
220 8C under an argon atmosphere. The mixture was stirred
and the temperature was allowed to rise to room
temperature. After 1 h, the solution solution was quenched
with methanol, and the solvents were evaporated. The crude
product was purified by chromatography on silica gel with
cyclohexane/ether (98/2) as eluent, and the product 20 was
obtained in 35% yield as yellow oil. An enantiomeric excess
of 64.6% was determined by chiral SFC analysis, using the
column chiralcel AS. TLC: Rf¼0.62 using cyclohexane/
Et2O(85/15). 1HNMR(CDCl3,400 MHz):d7.43–7.34(m,4H);
4.1.9. (R)-2-Phenyl-1,2,3,4-tetrahydro-[N-methoxy car-
bonyl]-quinoline (18). To a solution of 14 of 65.5% ee
(132.8 mg, 0.5 mmol, 1 equiv) in methanol (10 mL) was
added 2 mol% of palladium on activated charcoal. The

F. Amiot et al. / Tetrahedron 60 (2004) 8221–8231
8231
3289–3291. (b) Eisch, J. J.; Comfort, D. R. J. Organomet.
Chem. 1972, 38, 209–215. (c) Otsuji, Y.; Yutani, K.; Imoto, E.
Bull. Chem. Soc. Jpn. 1971, 44, 520–524. (d) Eisch, J. J.;
Comfort, D. R. J. Organomet. Chem. 1972, 43, C17–C19.
(e) Crawforth, C. E.; Meth-Cohn, O.; Russell, C. A. J. Chem.
Soc., Chem. Commun. 1972, 259–260. (f) Crawforth, C. E.;
Meth-Cohn, O.; Russell, C. A. J. Chem. Soc., Perkin Trans. 1
1972, 2807–2810. (g) Goldstein, S. W.; Dambek, P. J. Synthesis
1989, 221–222. (h) Guanti, G.; Perrozzi, S.; Riva, R.
Tetrahedron: Asymmetry 1998, 9, 3923–3927.
7.32–7.27 (m, 1H); 7.06–7.6.99 (m, 2H); 6.67 (t, 1H,
J¼7.4 Hz); 6.56 (d, 1H, J¼7.6 Hz); 4.46 (dd, 1H, J¼9.3,
3.4 Hz); 4.16 (s br, 1H); 2.99–2.89 (m, 1H); 7.15 (dt, 1H,
J¼16.3, 4.7 Hz); 2.17–2.10 (m, 1H); 2.06–1.97 (m, 1H).
13C NMR (CDCl3, 100 MHz): d 144.7; 129.3; 128.8; 128.6;
127.4; 126.9; 126.5; 121.0; 117.3; 114.1; 56.3; 30.9; 26.4.
IR: 3396; 2924; 1598; 1491; 1310; 1273; 831; 747;
698 cm21. MS-EI: m/z (relative intensity) 209 (92); 194
(15); 132 (100); 118 (17); 104 (13); 91 (25); 77 (24); 51
(10). Anal. calcd for C15H15N (209.29): C, 86.08; H, 7.22;
N, 6.69. Found: C, 84.90; H, 7.38; N, 5.44. Program of
chiral SFC: AS 10%-2-1-25%; elute: MeOH; pressure: 200
Bar; flow rate: 2 mL/min; 30 8C. [a]2D7¼231.4 (c¼1.26 in
CHCl3) for an ee of 64.6%. The absolute configuration was
assigned as (R) by analogy to the lit. data. (Lit.14
[a]2D5¼þ69.9 (c¼1 in CHCl3) for an ee of 72% for (S)
stereochemistry).
6. (a) Fraenkel, G.; Cooper, J. W.; Fink, C. M. Angew. Chem. Int.
Ed. Engl. 1970, 9, 523–525. (b) For reviews on the chemistry
of N-acyliminium ions see: Speckamp, W. N.; Hiemstra, H.
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 2, p 1047. Koning, H.;
Speckamp, W. N. Stereoselective synthesis, (Houben-Weyl);
Helmchen, G., Hoffman, R. W., Mulzer, J., Schaumann, E.,
Eds.; Georg Thieme: Stuttgart, 1996; Vol. E21, p 1953.
Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817. (c) Pilli, R. A.; Maldaner, A. O. Tetrahedron Lett. 2000,
41, 7843–7846.
Acknowledgements
The Swiss National Science Foundation, grant N8 2000-
68095.02, is acknowledged for the financial support.
7. Alexakis, A.; Mangeney, P.; Rezgui, F. Tetrahedron Lett.
1999, 40, 6241–6244.
8. Shibasaki, M.; Takamura, M.; Funabashi, K.; Kanai, M. J. Am.
Chem. Soc. 2000, 122, 6327–6328.
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