Highly enantioselective diethylzinc addition to imines employing readily available N-monosubstituted amino alcohols.

Article abstract of DOI:10.1021/ol025728u

An easily accessible chiral ligand 3c, which promoted diethylzinc addition to imines with 96-98% ee, has been found by finely screening N,N-disubstituted and N-monosubstituted amino alcohols. N-monosubstituted amino alcohols, on average, gave slightly hig

Full text of DOI:10.1021/ol025728u

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1399-1402
Highly Enantioselective Diethylzinc
Addition to Imines Employing Readily
Available N-Monosubstituted Amino
Alcohols
,†
,†
Hai-Le Zhang,† Xiao-Mei Zhang,† Liu-Zhu Gong,* Ai-Qiao Mi,* Xin Cui,†
Yao-Zhong Jiang,† Michael C. K. Choi,‡ and Albert S. C. Chan‡
Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, China, and Open Laboratory of
Chirotechnology of the Institute of Molecular Technology for Drug DiscoVery and
Synthesis and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic UniVersity, Hong Kong, China
gonglz@cioc.ac.cn
Received February 16, 2002
ABSTRACT
An easily accessible chiral ligand 3c, which promoted diethylzinc addition to imines with 96−98% ee, has been found by finely screening
N,N-disubstituted and N-monosubstituted amino alcohols. N-Monosubstituted amino alcohols, on average, gave slightly higher enantioselectivities
than their N,N-disubstituted analogues. These results imply that the restricted and rigid structure of amino alcohol is not the absolute requirement
for the highly enantioselective dialkylzinc addition to diphenylphosphinoylimines.
Optically active amines, serving as chiral intermediates or
starting materials, have been comprehensively applied in the
synthesis of some natural products and physiologically active
substances.1 They are also employed extensively as resolving
reagents and chiral auxiliaries in asymmetric synthesis.2 The
importance of chiral amines has fueled the development of
the new synthetic methodologies. Sucessful methods include
asymmetric hydrogenation of prochiral imines and enamides.3
The enantioselective nucleophilic addition of organometallic
reagents to imines has been investigated in recent years.1c,4
Enantioselective addition of dialkylzinc to imines is a
convenient route to optically active amines. There have been
several reports of the enantioselective addition of dialkylzinc
to imines employing chiral amino alcohols,5 polymeric chiral
amino alcohols,6 and chiral dendrimers7 as ligands. Recently,
Tomioka and co-workers reported their work on the copper-
amidophosphine catalyzed asymmetric addition of organozinc
(3) (a) Burk, M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996,
118, 5142. (b) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998,
63, 6084. (c) Zhang, F. Y.; Pai, C. C.; Chan, A. S. C. J. Am. Chem. Soc.
1998, 120, 5808. (d) Zhu, G. X.; Zhang, X. M. J. Org. Chem. 1998, 63,
9590. (e) Yan, Y. Y.; RajanBabu, T. V. Org. Lett. 2000, 2, 4137.
(4) (a) Denmark, S. E.; Nicaise, O. J.-C.; J. Chem. Soc., Chem. Commun.
1996, 999. (b) Denmark, S. E.; Nicaise, O. J.-C. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin, 1999; p 923. (c) Kobayashi, S.; Ishitani, H. Chem.
ReV. 1999, 99, 1069.
† Chengdu Institute of Organic Chemistry.
‡ The Hong Kong Polytechnic University.
(1) (a) Moser, H.; Rihs, G.; Sauter, H. Z. Naturforsch. B. 1982, 37(4),
451. (b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Enders, D.; Reinhold,
U. Tetrahedron: Asymmetry 1997, 8, 1895. (d) Johansson, A. Contemp.
Org. Synth. 1995, 2, 393.
(2) (a) Jacques, J.; Collet, A.; Wilen, S. H. In Enantiomers, Racemates,
and Resolution; John Wiley and Sons: New York, 1981. (b) Whitesell, J.
K. Chem. ReV. 1989, 89, 1581.
10.1021/ol025728u CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/20/2002

8
to imines with excellent results. Hoveyda, Snapper, and
In the presence of stoichiometric amount of N,N-disub-
stituted amino alcohols 2, we systematically examined the
effects of substituents bonded to the benzyl ring of the ligands
on the enantioselectivities by means of N-diphenylphos-
phinoyl benzalimine as a standard substrate. As can be seen
in Table 1, most of chiral N,N-disubstituted amino alcohols
their co-workers have also realized the catalytic asymmetric
diethylzinc addition to imines by means of chiral Zr
complexes.9 Many chiral amino alcohol ligands have been
developed for the diethylzinc addition to diphenylphos-
phinoylimines, but most of them are limited to compounds
containing a structurally rigid backbone. There is a trend in
previous reports that structurally constrained chiral â-amino
alcohols generally showed much higher enantioselectivities
than structurally flexible ones.5e-g However, structurally rigid
and restricted amino alcohols have inconveniences along with
their multistep synthesis5e,10 that make the process of
diethylzinc addition to imines to prepare the chiral amines
too expensive to compete with other families of chiral
ligands, especially when stoichiometric amounts were used.
Therefore the design and development of easily accessible
and economical chiral reagents are still a worthwhile project.
If the chiral reagents are cheap enough, the transformation
leading to chiral amines, even in the presence of stoichio-
metric amounts of such kinds of ligands, is also comparable
with the asymmetric catalytic process. In our previous work,
we have already presented the diethylzinc addition to
diphenylphosphinoylimines with up to 94% ee given by a
chiral ligand 1 derived from 1,2-diphenyl-2-aminoethanol
that has been made in large scale by a very cheap process.11
Herein, we would like to present our approach to a much
more easily available kind of ligand for the highly enantio-
selective diethylzinc addition to diphenylphosphinoylimines
with up to 98% ee, the best result observed so far for this
transformation. A finding that N-monosubstituted chiral
â-amino alcohols 3 generally gave slightly higher enantio-
selectivities than their N,N-disubstituted analogue 2 will also
be discussed. Chiral ligands were prepared from 1,2-
diphenyl-2-aminoethanol according to the literature. Treat-
ment of (1R,2S)-1,2-diphenyl-2-aminoethanol with aldehydes
followed by a reduction with NaBH4 gave the corresponding
monosubstituent amino alcohols 3a-f, which were subjected
to methylation with HCOOH/HCHO to give compounds 2a-
g.12
Table 1. Diethylzinc Addition to N-Diphenylphosphinoyl
Benzalimine 4a in the Presence of Chiral N,N-Disubstituted
Amino Alcohols 2a
entry
ligand
R
yield (%)b
ee (%)c
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
4-MeO
4-BnO
2,4,6-trimethyl
2-Br
3-Cl
4-Cl
94
63
93
35
87
94
80
95
92
84
91
95
93
93
2g
3,4-(OCH2O)-
a The reaction was carried out at room temperature in the presence of a
stoichiometric amount of amino alcohols for 48 h. b Isolated yields.
c Determined on HPLC; the absolute configuration is R.
2 could give good enantioselectivities with up to 95% ee.
The nitrogen substituents in the ligands had an obvious effect
on the enantioselectivity. It seemed that the ligands bearing
a bulkier R group in the benzene ring hindered the enantio-
selectivity. The ligand 2a, in which the R was a 4-methoxyl
group, promoted the reaction in 94% isolated yield with 95%
ee (entry 1), whereas 2b containing a bulkier R group of
(5) (a) Soai, K.; Hatanaka, T.; Miyazawa, T. J. Chem. Soc., Chem.
Commun. 1992, 1097. (b) Andersson, P. G.; Guijarro, D.; Tanner, D. Synlett
1996, 727. (c) Andersson, P. G.; Guijarro, D.; Tanner, D. J. Org. Chem.
1997, 62, 7364. (d) Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem.
1998, 63, 2530. (e) Brandt, P.; Hedberg, C.; Lawonn, K.; Pinho, P.;
Andersson, P. G. Chem. Eur. J. 1999, 5, 1692. (f) Jimeno, C.; Reddy, K.
S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A. Org. Lett. 2000, 2,
3157. (g) Zhang, X. M.; Lin, W. Q.; Gong, L. Z.; Mi, A. Q.; Cui, X.; Jiang,
Y. Z.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron Lett. 2002, 43, 1535.
(6) (a) Soai, K.; Suzuki, T.; Shono, T. J. Chem. Soc., Chem. Commun.
1994, 317. (b) Suzuki, T.; Narisada, N.; Shibata, T.; Soai, K. Tetrahedron:
Asymmetry 1996, 7, 2519.
(7) Suzuki, T.; Hirokawa, Y.; Ohtake, K.; Shibata, T.; Soai, K.
Tetrahedron: Asymmetry 1997, 8, 4033.
(8) Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122,
12055.
(9) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am.
Chem. Soc. 2001, 123, 984.
(10) Reddy, K. S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A.
Synthesis 2000, 165.
(11) Zhang, X. M.; Gong, L. Z.; Mi, A. Q.; Cui, X.; Jiang, Y. Z.; Choi,
M. C. K.; Chan, A. S. C. Tetrahedron Lett. 2001, 42, 6369.
(12) (a) Li, S. J.; Jiang, Y. Z.; Mi, A. Q. Tetrahedron: Asymmetry 1992,
3, 1467. (b) Mi, A. Q.; Wang, Z. Y.; Jiang, Y. Z. Tetrahedron: Asymmetry
1993, 4, 1957. (c) Mi, A. Q.; Wang, Z. Y.; Chen, Z. W.; Jiang, Y. Z.;
Chan. A. S. C.; Yang, T. K. Tetrahedron: Asymmetry 1995, 6, 2641. (d)
Jiang, Y. Z.; Zhou, X. G.; Hu, W. H.; Wu, L. J.; Mi, A. Q. Tetrahedron:
Asymmetry 1995, 6, 405. (e) Jiang, Y. Z.; Qin, Y.; Mi, A. Q.; Huang, Z. T.
Tetrahedron: Asymmetry 1994, 5, 1211.
Figure 1. Chiral â-amino alcohols evaluated in this study.
1400
Org. Lett., Vol. 4, No. 8, 2002

benzoxyl resulted in a slightly less stereochemical outcome
of 92% ee (entry 2). Further increase in the bulkiness of the
R group by replacement of 4-methoxylbenzyl 2a with a 2,4,6-
trimethylbenzyl group 2c led to a much lower ee value of
84% (entry 3). Most of ligands bearing a halogen on the
benzyl group possessed the excellent stereoselection property.
High enantioselectivities of 95% and 93% ee were provided
by 2e (R ) 3-Cl) and 2f (R ) 4-Cl), respectively (entries 5
and 6). The ligand 2d (R ) 2-Br) also afforded a good
enantioselectivity of 91% ee but only 35% isolated yield
(entry 4).
N,N-Disubstituted â-amino alcohols have been successfully
employed in the diethylzinc addition to carbonyl compounds
with extremely high enantioselectivity.13 Generally, an N,N-
disubstituent of the amino alcohol was the requirement for
getting high enantioselectivity. Among the approximately 260
individual chiral amino alcohols recently reviewed by Pu
and Yu for diethylzinc addition to aldehydes, only a few of
the N-monosubstituted amino alcohols have given more than
90% ee in the diethylzinc addition to aldehydes.14 The use
of N-monosubstituted â-amino alcohol in promoting the
diethylzinc addition to diphenylphosphinoylimines with high
enantioselectivity is also rare.6b The dramatic dependence
of the enantioselectivity on the size of the N,N-disubstituent
of the ligand prompted us to screen the N-substituent
carefully with a purpose of searching for an excellent chiral
ligand. It is encouraging that chiral amino alcohol 3a, in
which a methyl group was removed from the nitrogen as
compared with its N,N-disubstituted analogue 2a, provided
excellent enantioselectivity of 95% ee. This result indicated
that N-monosubstituted â-amino alcohol could also serve as
a good ligand for the diethylzinc addition to imine. Thus
we investigated the application of other N-monosubstituted
â-amino alcohols 3b-f in the above-mentioned reaction. As
seen in Table 2, all of the amino alcohols 3b-f afforded
higher or comparable enantioselectivties in comparison with
corresponding N,N-disubstituted compounds 2a-g. There
was a trend that a ligand bearing a bulkier R group induced
higher enantioselectivity. That was quite different from
findings in the cases of using N,N-disubstituted amino
alcohols 2 as chiral ligands. For example, ligand 3c contain-
ing a 2,4,6-trimethylbenzyl group generated the highest
enantioselectivity of 97% ee (Table 2, entry 3). However,
ligand 2c only resulted in 84% ee (Table 1, entry 3). If the
R group is a halogen, as shown in ligands 3d-f, the results
also supported the trend that the larger R group was
beneficial to the enantioselectivity. For instance, the ligand
3d processing a Br on the benzyl group gave an enantio-
selectivity of 95% ee (entry 5), better than those given by
3e-f in which R groups were Cl. However, in the cases of
using N,N-disubstituted amino alcohols 2d-f as promoters,
2e and 2f provided a higher stereochemical outcome than
2d did. In the presence of 50 mol % of the best ligand 3c,
high yield of 81% and 93% ee were afforded (entry 4).
With the optimal ligands 2a and 3c in hand, we extended
their application in the diethylzinc addition to other di-
phenylphosphinoylimines. The corresponding results are
recorded in Table 3. In the presence of ligand 2a, enantio-
Table 3. Asymmetric Diethylzinc Addition to Aromatic
N-Diphenylphosphinoyl Imines 4a-e Promoted by 2a and 3ca
Ar
imine
ligand
yield (%)b
ee (%)c
Ph
4a
2a
3c
3c
2a
3c
2a
3c
2a
3c
2a
3c
94
92
97
82
89
90
92
89
95
98
86
95
97
98d
95
97
95
97
96
98
94
96
4-MeOPh
piperonyl
4-MePh
4b
4c
4d
4e
Table 2. Diethylzinc Addition to N-Diphenylphosphinoyl
Benzalimine (4a) in the Presence of Chiral Amino Alcohols 3a
3-MePh
a The reaction was carried out at room temperature in the presence of a
stoichiometric amount of amino alcohols for 48 h, unless otherwise specified.
b Isolated yields based on imines. c Determined by HPLC. d The reaction
was performed in 1 mmol scale.
entry
ligands
R
yield (%)b
ee (%)c
selectivities from 94% to 96% ee values were obtained for
all of the imine substrates tested. Basically, the substituents
on the substrates had no obvious effect on the enantioselec-
tivity. Ligand 3c, on average, gave slightly higher enantio-
selectivities than ligand 2a did. For all of the substrates
examined, from 96% to 98% ee values were given by 3c;
1
2
3
4
5
6
7
3a
3b
3c
3c
3d
3e
3f
4-MeO
4-BnO
99
68
92
81
99
78
99
95
95
97
93d
95
94
94
2,4,6-trimethyl
2,4,6-trimethyl
2-Br
3-Cl
4-Cl
(13) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49. (b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833. (c) Soai, K.;
Shibata, T. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vol. 2, Chapter
26.1, p 911.
a The reaction was carried out at room temperature in the presence of a
stoichiometric amount of amino alcohols for 48 h. b Isolated yields.
c Determined on HPLC; the absolute configuration is R. d The reaction was
promoted by 50 mol % of ligand 3c.
(14) Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757.
Org. Lett., Vol. 4, No. 8, 2002
1401

not only were these the best results so far reported15 but also
the ligand 3c that we developed was the most easily
accessible. In addition, although a stoichiometric amount of
amino alcohol had to be used, the chiral ligand could be
recovered by flash chromatography.
a very easily accessible ligand 3c. These results implied that
the rigid and restricted structure of amino alcohol was not
the absolute requirement for the high enantioselective di-
alkylzinc addition to diphenylphosphinoylimine.
In summary, a family of N,N-disubstituted and N-mono-
substituted amino alcohols has been screened for the di-
ethylzinc addition to imines. In addition, we found that
N-monosubstituted amino alcohols gave slightly higher
enantioselectivities than N,N-disubstituted ones. An ex-
tremely high enantioselectivity of 98% ee was provided by
Acknowledgment. We are grateful for financial support
from the National Science Foundation of China (20102005)
and The Hong Kong Polytechnic University ASD Fund.
Supporting Information Available: Experimental pro-
cedure for the asymmetric diethylzinc addition to imines,
characterization of new amino alcohols, and HPLC analytical
data for chiral amides. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) Very recently, a structurally rigid chiral amino alcohol, which was
prepared by a nine-step reaction sequence from commercially available
compounds, could give results comparable with those of our ligand 3c for
the titled reaction in chlorobenzene. See: Pinho, P.; Andersson, P. G.
Tetrahedron 2001, 57, 1615.
OL025728U
1402
Org. Lett., Vol. 4, No. 8, 2002