Enantioselective additions of diethylzinc and diphenylzinc to aldehydes using 2-dialkyl-aminomethyl-2′-hydroxy-1,1′-binaphthyls

Article abstract of DOI:10.1021/ol026761j

(graph presented) A set of 2-dialkylaminomethyl-2′-hydroxy-1,1′-binaphthyls was prepared and used in the catalytic asymmetric additions of diethylzinc and diphenylzinc to various types of aldehydes. These binaphthyl-based axially chiral amino alcohols show high enantioselectivity in the addition of organozincs to aromatic and aliphatic aldehydes.

Full text of DOI:10.1021/ol026761j

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3759-3762
Enantioselective Additions of Diethylzinc
and Diphenylzinc to Aldehydes Using
2-Dialkyl-aminomethyl-2′-hydroxy-
1,1′-binaphthyls
Dong-Hyun Ko, Kyoung Hoon Kim, and Deok-Chan Ha*
Department of Chemistry, Korea UniVersity, Seoul 136-701, Korea
dechha@korea.ac.kr
Received August 21, 2002
ABSTRACT
A set of 2-dialkylaminomethyl-2′-hydroxy-1,1′-binaphthyls was prepared and used in the catalytic asymmetric additions of diethylzinc and
diphenylzinc to various types of aldehydes. These binaphthyl-based axially chiral amino alcohols show high enantioselectivity in the addition
of organozincs to aromatic and aliphatic aldehydes.
Asymmetric addition of organozincs to aldehydes is probably
the most successful and still vigorously pursued area in
asymmetric C-C bond formation.1 With the development
of diverse ligand structures and reaction conditions for the
highly selective catalytic reactions, chiral amino alcohols still
remain an attractive choice of catalyst, as a result of their
easy availability and simple reaction conditions. Since the
use of (S)-leucinol by Oguni, numerous amino alcohols,
mostly derived from natural chiral resources, have been
devised for the asymmetric organozinc addition.2,3 Despite
the enormous success of the axially chiral ligands in
asymmetric reactions, a limited number of amino alcohols
with 1,1′-biaryl backbone for the organozinc addition are
reported, including 1 and 2 (Figure 1).4
(1) Reviews on enantioselective diorganozinc additions to aldehydes: (a)
Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49-69.
(b) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-856. (c) Erdik, E.
Organozinc Reagents in Organic Synthesis; CRC Press: New York, 1996.
(d) Soai, K.; Shibata, T. In ComprensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; pp 911-
922. (e) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
(2) For selected reports on diethylzinc additions, see: (a) Oguni, N.;
Omi, T. Tetrahedron Lett. 1984, 25, 2823-2824. (b) Kitamura, M.; Suga,
S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071-6072. (c)
Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987, 109,
7111-7115. (d) Oguni, N.; Matsuda, Y.; Kaneko, T. J. Am. Chem. Soc.
1988, 110, 7877-7878. (e) Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org.
Chem. 1991, 56, 4264-4268. (f) Zhao, G.; Li, X.-G.; Wang, X.-R.
Tetrahedron: Asymmetry 2001, 12, 399-403. (g) DiMauro, F. F.; Ko-
zlowski, M. C. Org. Lett. 2001, 3, 3053-3059. (h) Wipf, P.; Wang, X.
Org. Lett. 2002, 4, 1197-1200. (i) Nugent, W. A. Org. Lett. 2002, 4, 2133-
2136.
Figure 1. 1,1′-Biaryl amino alcohols for organozinc addition.
In our search for ligands showing high enantioselectivity
for both aromatic and aliphatic aldehydes under convenient
10.1021/ol026761j CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/14/2002

reaction conditions with easy availability for both enanti-
omers of the ligand, we prepared axially chiral amino alcohol
3 from chiral binaphthol.
Amino alcohols 3a-f were conveniently prepared from
binaphthol bistriflate 4 through a three-step reaction sequence
(Scheme 1). Monomethoxycarbonylation of 4 gave ester 5
3). The use of n-BuLi together with 3a did not show any
appreciable changes in the results (entry 2 and 5).4a Despite
repeated experiments, a sharp decrease of the conversion
yield was observed by increasing the amount of 3a to 5 mol
% (entry 8).
Next, we investigated the substituent effect of the amino
part of 3b-f on the level of asymmetric induction in the
addition of Et2Zn to benzaldehyde (Table 2). Under the
Scheme 1. Synthesis of
2-Dialkylaminomethyl-2′-hydroxy-1,1′-binaphthyl Derivativesa
Table 2. Addition of Diethylzinc to Benzaldehyde Using
Ligands 3a-f
convn
(%)a,b
ee
(%)a,c
entry
ligand
1
2
3
4
5d
6
7
3a
3b
3c
3d
3d
3e
3f
89 (9)
77 (11)
8 (20)
93 (5)
90 (7)
87 (8)
89 (5)
91
87
25
94
95
94
93
a (a) cat. Pd(OAc)2, dppp, CO (1 atm), MeOH, DMSO, 60%;
(b) Me2AlNR2, toluene, quantitative yields; (c) LAH, THF, 62-
79%.
a Determined by chiral GC (Chiraldex G-TA column). b Number in the
parentheses refers to the amount of benzyl alcohol produced. c Absolute
configuration assigned by comparison to the literature. d Using 5.4 mol %
of n-BuLi.
in 60% yield,5 and the conversion to amide 66 followed by
LAH reduction provided amino alcohols 3a-f.
The amino alcohol 3a was chosen for the initial experi-
ments. Reaction between 2 equiv of diethylzinc and benz-
aldehyde was carried out in toluene for 24 h to give (R)-
(+)-1-phenyl-2-propanol (Table 1). The best result was
reaction condition optimized for 3a, di-n-butylamino deriva-
tive 3b showed decreased conversion (entry 2), and bulkier
dibenzylamino derivative 3c resulted in only 8% conversion
(entry 3). The pyrrolidine analogue 3d was the most reactive
(93% conversion) and selective (94% ee) ligand (entry 4).
Under the same condition, ligand 3d showed a high level
of nonlinear effect in the reaction between diethylzinc and
benzaldehyde, 60% ee and 92% ee of the alcohol products
with 20% ee and 50% ee of 3d, respectively.7 This is in
contrast to the structurally related 2, which was reported to
have a fully linear relationship between the enantiomeric
excess of 2 and the alcohol products.4b The difference can
Table 1. Addition of Diethylzinc to Benzaldehyde Using
Ligand 3a
mol %
Et2Zn
convn
(%)a,b
ee
(%)a,c
entry
(3a )
(equiv)
(3) For selected reports on diphenylzinc additions, see: (a) Zhang, H.;
Wue, F.; Mac, T. C.; Chan, K. S. J. Org. Chem. 1996, 51, 8002-8003. (b)
Huang, W.-S.; Pu, L. J. Org. Chem. 1999, 64, 4222-4223. (c) Huang, W.-
S.; Pu, L. Tetrahedron Lett. 2000, 41, 145-149. (d) Bolm, C.; Hermanns,
N.; Hildebrand, J. P.; Muniz, K. Angew. Chem., Int. Ed. 2000, 39, 3465-
3467. (e) Bolm, C.; Kesselgruber, M.; Hermanns, N.; Hildebrand, J. P.;
Raabe, G. Angew. Chem., Int. Ed. 2001, 40, 1488-1490.
(4) (a) Vyskocil, S.; Jaracz, S.; Smrcina, M.; Sticha, M.; Hanus, V.;
Polasek, M.; Kocovsky, P. J. Org. Chem. 1998, 63, 7727-7737. (b)
Bringmann, G.; Breuning, M. Tetrahedron: Asymmetry 1998, 9, 667-679.
(5) Ohta, T.; Ito, M.; Inagaki, K.; Takaya, H. Tetrahedron Lett. 1993,
34, 1615-1616.
(6) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
18, 4171-4174. (b) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun.
1982, 12, 989-993.
1
2
2
3
3
3
3
5
2
2
2
2
2
1.2
2
75 (11)
78 (11)
33 (9)
89 (9)
88 (7)
71 (9)
45 (17)
87
88
88
91
92
93
88
2d
3e
4
5d
6
7
a Determined by chiral GC (Chiraldex G-TA column). b Number in the
parentheses refers to the amount of benzyl alcohol produced. c Absolute
configuration assigned by comparison to the literature. d Using 5.4 mol %
of n-BuLi. e Reaction was carried out at 0 °C.
(7) (a) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S. H.; Agami, C.;
Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2353-2357. (b) Soai, K.;
Shibata, T.; Morioka, H.; Choji, K. Nature 1995, 378, 767-768. (c)
Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989,
111, 4028-4036. (d) Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am.
Chem. Soc. 1998, 120, 9800-9809. (e) Chen, Y. K.; Costa, A. M.; Walsh,
P. J. J. Am. Chem. Soc. 2001, 123, 5378-5379.
obtained with 3 mol % of 3a at room temperature (entry 4).
The ethylation at 0 °C was quite slow, and 58% of the
starting benzaldehyde remained unreacted after 24 h (entry
3760
Org. Lett., Vol. 4, No. 21, 2002

be due to the difficulty of 2 in forming the heterochiral
dinuclear catalyst precursor due to two relatively bulky
n-butyl groups, compared with the pyrrolidinyl group in 3d.7c
The use of ligand 3d in the ethylation was extended to
other aldehydes (Table 3). High levels of secondary alcohol
Table 4. Addition of Diphenylzinc to p-Anisaldehyde Using
Ligands 3a-f
t
isolated
ee
(%)a,b
Table 3. Addition of Diethylzinc to Aldehydes Using
Ligand 3d
entry
ligand
(h)
yield (%)
1
3a
3b
3c
3d
3d
3e
3f
1
1
71
93
97
95
94
97
75
88
87
95
94
90
98
98
2
3
1
4
5c
1
isolated
ee
(%)a
10
1
entry
R
yield (%)
6
7d
94b
94c
93d
96c
99b
96c
96c
94e
98e
86c
76c
92f
24
1
Ph
89
97
97
95
97
92
95
96
89
95
97
84
2
p-MeO-Ph
o-Cl-Ph
a Determined by HPLC (Chiralcel OJ column). b Absolute configuration
assigned by comparison to the literatures. c Using 5 mol % of catalyst 3f.
d A mixture of Ph2Zn (1 equiv) and Et2Zn (2 equiv) was used.
3
4
m-Cl-Ph
5
p-Cl-Ph
6
1-naphthyl
2-naphthyl
hexyl
7
Excellent yields and enantiomeric excesses were accom-
plished with aromatic aldehydes (entries 1-6), but moderate
enantioselectivities were obtained for R,â-unsaturated and
aliphatic aldehydes (entries 7-10). Unlike with the reaction
between benzaldehyde and diethylzinc catalyzed by 3d, weak
nonlinear effect was observed in the reaction between
p-tolualdehyde and diphenylzinc catalyzed by 3f (32% ee
and 67% ee of the product alcohols with the use of 25% ee
and 50% ee of 3f, respectively).
8
9
cyclohexyl
trans-Ph-CHdCH
Ph-CtC
10
11
12
TIPS-CtC
a Absolute configuration assigned by comparison to the literatures.
b Determined by chiral GC (Chiraldex G-TA column). c Determined by
chiral HPLC (Chiralcel OD column). d Determined by chiral HPLC [(R,R)-
Welk-O 1 column]. e Determined by chiral GC (Chiraldex G-TA column)
of the corresponding acetate derivatives. f Determined by 19F NMR of the
corresponding (R)-MTPA ester derivative.
In summary, we have prepared a series of chiral amino
alcohols from (R)-binaphthol and applied them to the
asymmetric additions of organozincs to various aromatic,
formation and excellent enantiomeric excess were obtained
for both aromatic (entries 1-7) and aliphatic aldehydes
(entries 8 and 9).
Table 5. Addition of Diphenylzinc to Aldehydes Using
Ligand 3f
The enantioselectivities for substituted benzaldehydes were
generally high, and a slight decrease of the selectivity was
observed when the substituent was positioned closer to the
aldehyde group as shown in the case of chlorobenzaldehydes
(entries 3-5). Ligand 3d was also applied for the ethylation
of R,â-unsaturated aldehydes, but with lower selectivity
compared with the cases of aromatic and aliphatic aldehydes
(entries 10 and 11). Enantioselectivity in the case of
propargyl aldehyde was improved by introducing bulky TIPS
group (entry 12).
Enantioselective addition of diphenylzinc to aldehydes is
more challenging because of the rapid competitive uncata-
lyzed phenylation. One of the methods to suppress the
undesired background reaction is to use a mixture of
diphenylzinc and diethylzinc.3d Ligands 3a-f were screened
again for the phenylation of p-anisaldehyde using diphen-
ylzinc only (Table 4). The best result was obtained with the
morpholino derivative 3f (entry 6). Use of the mixture of
diphenylzinc and diethylzinc gave similar enantioselectivity,
but with much decreased isolated yield (entry 7).
isolated
% ee
(config)a
entry
R
yield (%)
1
p-MeO-Ph
p-Me-Ph
97
97
95
95
97
98
72
93
94
97
98b (R)
97c (R)
96c (R)
92d (R)
95e (R)
97c (R)
85f (R)
75c (S)
66c (S)
68g (S)
2
3
o-Cl-Ph
4
m-Cl-Ph
5
p-Cl-Ph
6
2-naphthyl
TIPS-CtC
trans-Ph-CHdCH
hexyl
7
8
9
10
cyclohexyl
a Absolute configuration assigned by comparison to the literatures.
b Determined by HPLC (Chiralcel OJ column). c Determined by HPLC
(Chiralcel OD column). d Determined by HPLC [(R,R)-Welk-O 1 column].
e Determined by HPLC (Chiralcel OB-H column). f Determined by 1H NMR
of the corresponding (R)-MTPA ester derivatives. g Determined by HPLC
(Chiralcel AD-H column).
Various aromatic and aliphatic aldehydes were studied for
the phenylation with 10 mol % of 3f at 0 °C (Table 5).
Org. Lett., Vol. 4, No. 21, 2002
3761

aliphatic, and unsaturated aldehydes. Excellent enantio-
selectivities and yields were accomplished in the ethylations
of aromatic and aliphatic aldehydes with Et2Zn at room
temperature. Also, similar results were obtained in the
phenylations of aromatic aldehydes by the use of Ph2Zn only.
These amino alcohols may constitute a new set of efficient
catalysts in terms of convenient ligand preparations, simple
reaction conditions, and high asymmetric induction.
Acknowledgment. This work was financially supported
by the Center for Molecular Design and Synthesis (CMDS)
at KAIST.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026761J
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Org. Lett., Vol. 4, No. 21, 2002