The synthesis of new optically active 2-methylquinoline derivatives and their application in the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(01)00016-7

Homochiral 2-methylquinoline derivatives have been synthesized and applied in the enantioselective addition of diethylzinc to aldehydes. Good yields and enantiomeric excesses of up to 91.4% were observed in these reactions.

Full text of DOI:10.1016/S0957-4166(01)00016-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 381–385
The synthesis of new optically active 2-methylquinoline
derivatives and their application in the enantioselective addition
of diethylzinc to aldehydes
a
a
a,
b
Qianyong Xu, Guoxing Wang, Xinfu Pan * and Albert S. C. Chan
a
Department of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
b
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, PR China
Received 13 November 2000; accepted 4 January 2001
Abstract—Homochiral 2-methylquinoline derivatives have been synthesized and applied in the enantioselective addition of
diethylzinc to aldehydes. Good yields and enantiomeric excesses of up to 91.4% were observed in these reactions. © 2001
Published by Elsevier Science Ltd.
hols with low enantioselectivity by treatment of
benzaldehyde with methylmagnesium iodide in the
presence of N,N-dimethylbornylamine. A significant
1
. Introduction
2
One of the most important and fundamental synthetic
procedures for the establishment of carbonꢀcarbon
bond stereoselectivity is the enantioselective addition of
organometallic reagents to aldehydes affording chiral
improvement has been achieved by using organozinc
compounds as alkylating agents. Since uncoordinated
organozinc compounds are virtually inert, the reaction
requires a compound to coordinate to the metal atom
to enhance nucleophilicity. Due to the increased reac-
tivity of the reagent when it is involved in the coordi-
nated complex, a catalytic amount of the coordinating
ligand can be used. For this purpose, many chiral
ligands, mostly with 1,2-functionalities, have been
1
secondary alcohols. This structural feature is part of
many natural products or can serve as an important
synthetic precursor to various other functionalities,
such as halide, amine, ester and ether. Effective enan-
tioselective routes to sec-alcohols are therefore of great
synthetic value.
3,4
designed and synthesized. Despite the variety of chi-
ral ligands that have been synthesized, the design and
development of cost-effective catalysts that exhibit
The first reported enantioselective alkylation of alde-
hydes was performed by Betti, who obtained sec-alco-
Scheme 1. Reagents and conditions: (i) BuLi, ether, 0°C; (ii) (+)-camphor, ether, 0°C; (iii) (−)-menthone, ether, 0°C.
*
Corresponding author. E-mail: panxf@lzu.edu.cn
0
957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00016-7

3
82
Q. Xu et al. / Tetrahedron: Asymmetry 12 (2001) 381–385
tions were run in non-polar solvents than in polar
solvents. If a non-polar solvent was used, a solvent
effect was detectable but not very significant. At 0°C
the use of toluene, benzene, ether, hexane, benzene/hex-
ane or toluene/hexane as solvents gave e.e.s ranging
from 76.8 to 83.1% (entries 4–9). Toluene/hexane was
found to be the preferred solvent for this addition
reaction since it gave the best yield and enantioselectiv-
ity (entry 9).
Scheme 2.
high reactivity and enantioselectivity remain an active
research subject.
5
Several quinoline derived aminoalcohol or (+)-cam-
phor and (−)-menthone derived b-amino alcohols have
been synthesized and used in the enantioselective alky-
lation of aldehydes. However, to our knowledge, no
chiral ligands derived from quinoline and (+)-camphor
or (−)-menthone have been reported. Herein, we first
report the syntheses of chiral ligands derived from
6
The effect of temperature on the enantioselectivity of
the reaction was also detectable, albeit not very large,
with e.e. values tending to increase with decreasing
temperature (entries 9–11). For convenience a tempera-
ture of 0°C was chosen and the toluene/hexane mixture
(
1:1, v/v) was adopted as the solvent system.
2-methylquinoline, (+)-camphor and (−)-menthone, and
their applications in the enantioselective addition of
diethylzinc to aldehydes.
Next, we examined the effect of catalyst loading and
the results are summarized in Table 2. It is interesting
to find that the amounts of the two ligands have
different effects on the e.e. values. When ligand 1 was
used, the e.e. values of (R)-1-phenylpropan-1-ol
increased by increasing the amount of catalyst. For
example, the enantioselective addition of diethylzinc to
benzaldehyde in toluene/hexane (1:1, v/v) catalyzed by
either 5, 10, 15 or 20 mol% of ligand 1 afforded
2
. Results and discussion
The syntheses of the chiral ligands 1 and 2 are shown in
Scheme 1. 2-Methylquinoline was first lithiated with7
BuLi in ether at 0°C to give 2-quinolylmethyllithium,
followed by trapping with (+)-camphor or (−)-men-
thone to produce compounds 1 and 2 in nearly quanti-
(
R)-1-phenylpropan-1-ol in e.e.s of 72.2, 78.2, 82.2 and
1
83.1%, respectively (entries 1–4). When this reaction
was catalyzed by 5, 10 or 20 mol% of ligand 2, the
(S)-isomer was produced in e.e.s of 64.5, 63.4 and
tative yields as single diastereoisomers, as shown by H
NMR analyses. The configurations shown in Scheme 1
6
are the same as those reported previously.
2
4.4%, respectively (entries 5–7). Other solvent systems
such as benzene/hexane, benzene and toluene were
examined for ligand 2 and similar results were obtained
The enantioselective addition of diethylzinc to alde-
hydes catalyzed by the synthesized chiral ligands 1 and
(
entries 8–14). This phenomenon is not easy to under-
2
is shown in Scheme 2. It has been reported that the
stand, but it probably arises from a non-stereoselective
ethyl transfer to aldehyde promoted by zinc coordina-
solvent has a great effect on the enantioselectivity and
8
yield. Therefore we first investigated the effect of sol-
9
vent on the enantioselectivity of the addition of
diethylzinc to benzaldehyde using ligand 1 as catalyst.
The effect of temperature was also investigated, and the
results of this study are shown in Table 1.
tion to the nitrogen atom of the catalyst.
Using the optimized reaction conditions, the addition
of diethylzinc to various aromatic and aliphatic alde-
hydes catalyzed by both chiral ligands 1 and 2 was
examined, and the results are summarized in Table 3. It
As expected, the e.e. values were better when the reac-
Table 1. The effect of solvents and temperature on the asymmetric addition of diethylzinc to benzaldehyde with 1 as a
a
catalyst
Entry
Solvent
Temperature (°C)b
Yield (%)c
E.e. (%) (config.)d
1
2
3
4
5
6
7
8
9
Dichloromethane
Acetonitrile
THF
Toluene
Benzene
Ether
Hexane
Benzene/hexane (1:1)
Toluene/hexane (1:1)
Toluene/hexane (1:1)
Toluene/hexane (1:1)
0
0
0
0
0
0
0
0
73
69
56
95
96
91
95
94
96
94
93
48.7 (R)
51.7 (R)
67.6 (R)
76.9 (R)
76.8 (R)
79.3 (R)
77.6 (R)
80.9 (R)
83.1 (R)
82.4 (R)
86.4 (R)
0
rt
−20
1
1
0
1
a
b
c
Catalyst/benzaldehyde/Et Zn=0.2/1.0/2.0 (mmol).
The reactions were completed at the indicated temperature for 4 h then warmed to rt gradually with stirring for 12 h.
Based on isolated product.
2
d
The e.e. values were determined by GLC.

Q. Xu et al. / Tetrahedron: Asymmetry 12 (2001) 381–385
383
Table 2. The effect of chiral ligands on the asymmetric
electron withdrawing group when catalysed by ligand 1
entries 3, 7, 9, 11 and 13). However, the addition
a
addition of diethylzinc to benzaldehyde
(
reactions catalysed by ligand 2 for all the substituted
Entry Ligand
mol%)
Solvent
Yield (%)b E.e. (%)
(config.)
aromatic aldehydes occurred with low enantioselectivity
c
(
(
entries 2, 4, 6, 8, 10, 12, 14, 16 and 18) and for
aliphatic aldehydes, the enantioselectivities of the reac-
tion are generally low (entries 19–26).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1 (20)
(15)
(10)
(5)
2 (20)
(10)
(5)
(20)
(10)
(5)
(20)
(5)
Toluene/hexane (1:1) 96
Toluene/hexane (1:1) 94
Toluene/hexane (1:1) 94
Toluene/hexane (1:1) 91
Toluene/hexane (1:1) 92
Toluene/hexane (1:1) 90
Toluene/hexane (1:1) 93
Benzene/hexane (1:1) 88
Benzene/hexane (1:1) 90
Benzene/hexane (1:1) 85
83.1 (R)
82.2 (R)
78.2 (R)
72.2 (R)
24.4 (S)
63.4 (S)
64.5 (S)
26.1 (S)
54.1 (S)
56.7 (S)
41.4 (S)
48.9 (S)
48.7 (S)
53.3 (S)
From all the above results, it can be seen that ligand 1
induced (R)-enriched products and ligand 2 induced
(
S)-enriched products. It is recognized that the actual
catalyst is in situ formed ethylzinc aminoalkoxide.
When the ethylzinc aminoalkoxide A is formed from 1
and diethylzinc, the O-Zn linkage should be arranged
to the syn-position of the norbornane skeleton (Fig. 1).
Due to the steric repulsion between the 1-methyl of
norbornane and the quinoline ring, the less hindered
Re-face of the zinc atom might be more reactive
towards the aldehyde oxygen leading to TS-1, and the
0
1
2
3
4
Benzene
Benzene
Toluene
Toluene
91
89
93
91
(20)
(5)
a
The reactions were run at 0°C for 4 h and then warmed up to rt
gradually with stirring for 12 h. Benzaldehyde/Et Zn=1.0/2.0
(
R)-enriched product was obtained. In contrast, when
2
the ethylzinc complex B is formed from 2 and diethyl-
zinc, the O-Zn linkage should be arranged to the anti-
position of the menthol skeleton. Because of steric
hindrance between the quinoline ring and the ethyl
group on zinc, the less hindered side was the Si-face of
the zinc atom, which coordinates with the aldehyde
oxygen leading to transition state TS-2, and an (S)-
enriched product was obtained. The extreme difference
(
mmol).
b
c
Based on isolated product.
E.e. values were determined by GLC.
can be seen from the results that the enantioselectivity
of the addition of diethylzinc to aldehydes with an
electron donating group in the para-position of the
aromatic ring is higher than to an aldehyde with an
a
Table 3. Enantioselective addition of diethylzinc to aldehydes
Entry
Substrate
Ligand (mol%)
Yield (%)b
E.e. (%) (config.)c
1
2
3
4
5
6
7
8
9
Benzaldehyde
1 (20)
2 (5)
1 (20)
2 (5)
1 (20)
2 (5)
1 (20)
2 (5)
1 (20)
2 (5)
1 (20)
2 (5)
1 (20)
2 (5)
1 (20)
2 (5)
1 (20)
2 (5)
1 (20)
2 (5)
1 (20)
2 (5)
1 (20)
2 (5)
96
93
90
87
95
94
89
93
93
96
97
95
90
91
94
87
90
93
92
93
70
74
78
85
83
89
83.1 (R)
64.5 (S)
76.5 (R)
53.9 (S)
80.2 (R)
54.5 (S)
91.4 (R)
63.9 (S)
83.5 (R)
60.9 (S)
p-Chlorobenzaldehyde
o-Anisaldehyde
p-Anisaldehyde
p-Tolualdehyde
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
d
4-(Dimethylamino)benzaldehyde
3,4-Dimethoxybenzaldehyde
1-Naphthaldehyde
2-Naphthaldehyde
trans-Cinnamaldehyde
Nonylaldehyde
88.5 (R)
58.9 (S)d
d
86.8 (R)
56.0 (S)d
d
89.3 (R)
72.5 (S)d
d
78.6 (R)
64.3 (S)d
d
74.5 (R)
69.1 (S)d
e
38.5 (R)
40.4 (S)
29.7 (R)
31.1 (S)
42.7 (R)
44.2 (S)
e
e
Dodecylaldehyde
e
e
Cyclohexanecarboxaldehyde
1 (20)
2 (5)
e
a
b
c
The reactions were run at 0°C for 4 h and then warmed up to rt gradually with stirring for 12 h. Aldehyde/Et Zn=1.0/2.0 (mmol).
Based on isolated product.
Except as noted, the e.e. values were determined by GLC.
Determined by HPLC.
Determined by GLC after acetylation.
2
d
e

3
84
Q. Xu et al. / Tetrahedron: Asymmetry 12 (2001) 381–385
in the reactivity between Re- and Si-face in the
aminoalkoxide A results in a highly enantioselective
formation of alcohols.
CB capillary column on a Varian CP-3380 GC instru-
ment with FID as detector and nitrogen as carrier gas
or using HPLC with a Chiralcel OD column on a
Varian SD-200 HPLC instrument with UV detector
and hexane/2-propanol as eluent. The configuration
establishment of the products was based on the com-
parison of the direction of specific rotation with known
compounds. All solvents used were dried by standard
methods and aldehydes were purified using standard,
published methods before use.
In conclusion, we have demonstrated that chiral ligands
1
and 2 can be easily prepared from (+)-camphor and
(
−)-menthone, and that they are effective catalysts for
the enantioselective addition of diethylzinc to alde-
hydes. Further work is in progress in this laboratory
with the aim of expanding the use of these inexpensive
chiral compounds to other enantioselective processes.
3
.2. The synthesis of 2-methylquinoline derived chiral
ligands 1, 2
3
3
. Experimental
.1. General
3
.2.1. The synthesis of 2-methylquinoline derived chiral
ligand 1. To a 100 mL flame-dried three-neck flask
under an argon atmosphere were added 2-methylquino-
line (1.34 mL, 10 mmol) and anhydrous ether (30 mL).
This solution was cooled to 0°C and 2.4 M butyllithium
in hexane (4.3 mL, 10.4 mmol) was added using a
pressure-equalizing dropping funnel over 15 min with
stirring. The cooling bath was removed and the solu-
tion was allowed to stir for 1 h while the temperature
rose to ambient. A solution of (+)-camphor (1.51 g, 10
mmol) in ether (20 mL) was added over 15 min with
vigorous stirring while the temperature cooled to 0°C.
The mixture was stirred for additional 2 h and
All reactions were carried out under an Ar atmosphere.
Melting points were measured on a Kofler melting
1
13
apparatus and are uncorrected. H and C NMR
spectra were measured on a Bruker AM-400 NMR
spectrometer with TMS as an internal reference. Elec-
tron ionization mass spectra were obtained on a
Hewlett–Packard HP5988A mass spectrometer. Positive
ion FAB mass spectra as 3-nitrobenzyl alcohol matrix
were recorded on a VG ZAB-HS mass spectrometer.
Elemental analyses were performed on a Carlo–Erba-
1
106 elemental analyzer. Optical rotations were mea-
hydrolyzed with a saturated aqueous NH Cl solution.
4
sured on a JASCO J-20C automatic polarimeter.
Enantiomeric excess (e.e.) determination was carried
out using GLC with a Chrompack CP-Chirasil-DEX
When decomposition was complete, the ether layer was
separated, and the water layer was extracted with ethyl
acetate (3×20 mL). The combined organic layers were
Figure 1.

Q. Xu et al. / Tetrahedron: Asymmetry 12 (2001) 381–385
385
washed with brine and dried over anhydrous Na SO ,
combined organic layers were washed with brine, dried
2
4
and the solvent was evaporated under reduced pressure.
The crude product was purified by flash chromatogra-
phy to give a white solid (2.80 g, 95% yield). Mp 88–89;
over anhydrous Na SO4 and concentrated under
2
reduced pressure. After purification by flash chro-
matography, the enantiomeric excess was determined
by GLC.
2
0
1
[
h] =−37.8 (c 1.01, CHCl ). H NMR (CDCl , l
D 3 3
ppm): 0.56 (s, 3H), 0.64 (s, 3H), 1.17 (s, 3H), 1.10–1.15
m, 1H), 1.41–1.49 (m, 2H), 1.52–1.58 (m, 1H), 1.71–
(
1
7
7
.78 (m, 2H), 2.14 (m, 1H), 3.17 (s, 2H), 6.75 (br, 1H),
.33 (d, J=8.4 Hz, 1H), 7.51 (m, 1H), 7.69 (m, 1H),
.80 (d, J=8.4 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 8.12
References
13
(
d, J=8.4 Hz, 1H). C NMR (CDCl , l ppm): 11.27,
1. For review see: (a) Noyori, R.; Kitamura, M. Angew.
Chem., Int. Ed. Engl. 1991, 30, 49; (b) Soai, K.; Niwa, S.
Chem. Rev. 1992, 92, 833; (c) Blaser, H.-U. Chem. Rev.
1992, 92, 935; (d) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; Wiley: New York, 1994.
2. (a) Betti, M.; Lucchi, E. Boll. Sci. Fac. Chim. Ind. Bologna
1940, 1–2, 2; (b) Tarbell, D. S.; Paulson, M. C. J. Am.
Chem. Soc. 1942, 64, 2842.
3
2
5
1
2
1.04, 21.48, 22.23, 30.97, 45.07, 45.57, 47.53, 49.47,
2.50, 81.45, 122.91, 126.08, 126.67, 127.50, 128.71,
+
29.75, 136.71, 146.68, 161.27; MS m/z (EI): 295 (M ),
80, 185, 143; positive ion FAB mass spectra m/z: 296
+
(
M +H). Anal. calcd for C H NO: C, 81.31; H, 8.53;
20
25
N, 4.74. Found: C, 81.23; H, 8.44; N, 4.89%.
3
.2.2. The synthesis of 2-methylquinoline derived chiral
3. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996,
96, 835.
ligand 2. Prepared from 1.53 g of (−)-menthone in a
similar manner to that described above to give a white
solid (2.67 g, 90% yield). Mp 137–138; [h] =−61.6 (c
4. (a) Kawanami, Y.; Mitsuie, T.; Miki, M.; Sakamoto, T.;
Nishitani, K. Tetrahedron 2000, 56, 175; (b) Sola, L.;
Reddy, K. S.; Vidal-Feran, A.; Moyano, A.; Pericas, M.
A.; Riera, A.; Alvarez-Larena, A.; Piniella, J.-F. J. Org.
Chem. 1998, 63, 7078; (c) Base, S. J.; Kim, S.-W.; Hyeon,
T.; Kim, B. M. Chem. Commun. 2000, 31; (d) Paleo, M.
R.; Cabeza, I.; Sardina, F. J. J. Org. Chem. 2000, 65, 2108;
(e) Kitamura, M.; Oka, H.; Noyori, R. Tetrahedron 1999,
55, 3605; (f) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R.
J. Am. Chem. Soc. 1998, 120, 9800.
5. (a) Shibata, T.; Choji, K.; Hayase, T.; Aizu, Y.; Soai, K.
Chem. Commun. 1996, 1235; (b) Shibata, T.; Choji, K.;
Morioka, H.; Hayase, T.; Soai, K. Chem. Commun. 1996,
751.
6. (a) Kwong, H.-L.; Lee, W.-S. Tetrahedron: Asymmetry
1999, 10, 3791; (b) Nugent, W. A. Chem. Commun. 1999,
1369; (c) Genov, M.; Kostova, K.; Dimitrov, V. Tetra-
hedron: Asymmetry 1997, 8, 1869; (d) Mellao, M. L.;
Vasconcellos, M. L. A. A. Tetrahedron: Asymmetry 1996,
7, 1607; (e) Knollmuller, M.; Ferencic, M.; Gartner, P.;
Mereiter, K.; Noe, C. R. Tetrahedron: Asymmetry 1998, 9,
4009; (f) Knollmuller, M.; Ferencic, M.; Gartner, P. Tetra-
hedron: Asymmetry 1999, 10, 3969.
2
0
D
1
1
.14, CHCl3); H NMR (CDCl , l ppm): 0.66 (d,
3
J=6.5 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 1.02 (d, J=6.5
Hz, 3H), 0.87–0.91 (m, 1H), 1.10–1.12 (m, 1H), 1.24–
1
2
.27 (m, 1H), 1.44–1.48 (m, 1H), 1.61–1.70 (m, 4H),
.36 (m, 1H), 3.14 (d, J=13.8 Hz, 1H), 3.47 (d, J=13.8
Hz, 1H), 5.30 (br, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.53
m, 1H), 7.71 (m, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.99 (d,
(
1
3
J=8.4 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H). C NMR
CDCl , l ppm): 18.47, 21.40, 22.69, 24.00, 28.31,
(
2
1
3
6.98, 36.08, 47.89, 48.22, 51.33, 75.60, 124.29, 126.67,
27.49, 128.53, 129.22, 130.36, 137.24, 147.84, 162.53.
+
MS m/z (EI): 297 (M ), 282, 254, 240, 212, 143; positive
ion FAB mass spectra m/z: 298 (M +H). Anal. calcd
for C H NO: C, 80.76; H, 9.15; N, 4.71. Found: C,
+
2
0
27
80.67; H, 9.24; N, 4.93%.
3
.3. General procedure for the asymmetric addition of
diethylzinc to benzaldehyde
To a solution of ligand 1 (0.20 mmol) in toluene (2 mL)
and hexane (2 mL) at 0°C was added a 1.0 M solution
(
2 mL, 2.0 mmol) of diethylzinc in hexane. After stir-
7. (a) Brzezinski, J. Z.; Epsztajn, J.; Michalski, T. J. Tetra-
hedron Lett. 1976, 17, 4635; (b) Jones, A. M.; Russell, C.
A.; Skidmore, S. J. Chem. Soc. (C) 1969, 2245.
ring for 30 min at 0°C, freshly distilled benzaldehyde (1
mmol) was added. The reaction mixture was stirred for
4
h at 0°C then allowed to warm to room temperature
gradually with stirring for 12 h. After the addition of
N HCl (10 mL), the phases were separated. The water
8. Zhang, F. Y.; Yip, C. W.; Cao, R.; Chan, A. S. C.
Tetrahedron: Asymmetry 1997, 8, 585.
9. Patti, A.; Nicolosi, G.; Howell, J. A. S.; Humphries, K.
Tetrahedron: Asymmetry 1998, 9, 4381.
1
layer was extracted with ethyl acetate (5 mL). The
.