Highly enantioselective addition of diphenylzinc to aliphatic and aromatic aldehydes catalyzed by a readily available H8-binol derivative

Article abstract of DOI:10.1002/anie.200503206

(Chemical Equation Presented) All sorts of aldehydes 2 (R = aryl, vinyl, branched, and linear alkyl) undergo the highly enantioselective addition of diphenylzinc (1) in the presence of catalytic (S)-4 to give α-substituted benzyl alcohols 3 in high yields. In contrast to previous catalysts, no additive is required, the reaction is carried out at room temperature, and the reaction is equally effective with linear aldehydes.

Full text of DOI:10.1002/anie.200503206

Angewandte
Chemie
Asymmetric Addition
DOI: 10.1002/anie.200503206
Highly Enantioselective Addition of Diphenylzinc
to Aliphatic and Aromatic Aldehydes Catalyzed
by a Readily Available H -Binol Derivative**
8
Ying-Chuan Qin and Lin Pu*
Chiral a-substituted benzyl alcohols are ubiquitous in the
structure of organic compounds. A straightforward synthesis
of these compounds involves the nucleophilic
addition of a phenyl–metal reagent to an
aldehyde which produces a carbon–carbon
bond and a stereogenic center simultane-
ously. Because of the high activity of phenyl-
lithium and phenyl Grignard reagents, their
asymmetric reactions with aldehydes need to
be conducted in the presence of stoichiomet-
[
1–5]
ric or excess amount of chiral reagents.
Among the catalytic asymmetric additions of the phenyl
[
6–16]
group to aldehydes,
much attention in recent years as the reagent is readily
available.
the use of diphenylzinc has received
[
10–16]
In 1997, Fu and co-workers reported the
addition of diphenylzinc to aldehydes catalyzed by 1 with
[*] Y.-C. Qin, Prof. L. Pu
Department of Chemistry
University of Virginia
Charlottesville, VA 22904-4319 (USA)
Fax: (+1)434-924-3710
E-mail: lp6n@virginia.edu
[**] The partial support of this work from the National Institutes of
Health (R01M58454/R01EB002037-05) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
273

Communications
[
10]
moderate enantioselectivity. In 1999, we found that com-
Table 1: Results for the (S)-4-catalyzed addition of diphenylzinc to
valeraldehyde under various conditions.
[
a]
[
11]
pound 2 showed high enantioselectivity for this reaction. At
about the same time, Bolm and co-workers reported good
[
12]
results with the use of 3. Other chiral ligands were also
[
13–16]
developed for the asymmetric addition of diphenylzinc.
A few of these compounds catalyze the addition of diphe-
nylzinc to aromatic and a-branched aliphatic aldehydes with
high enantioselectivity (> 90% ee). However, the enantiose-
lectivity for the addition to linear aliphatic aldehydes is
generally lower, and no catalyst has been reported to give
over 90% ee for the addition of diphenylzinc to a linear
aliphatic aldehyde. Thus, the search for generally applicable
catalysts for the asymmetric addition of diphenylzinc to
aldehydes continues.
We have been interested in using 2,2’-dihydroxy-1,1’-
binaphthyl (binol) and its derivatives in asymmetric processes
such as catalysis and sensing. Recently, we reported a one-
step synthesis of the 3,3’-substituted partially hydrogenated
[
b,c]
Entry
(S)-4
[mol%]
SolventPh
CH Cl
2Zn
[equiv]
ee [%]
1
2
3
4
5
6
10
10
10
10
10
10
10
10
5
1.2
1.2
1.2
1.2
1.2
1.0
1.6
1.6
1.2
1.4
35
38
39
92
93
91
89
91
84
87
2
2
toluene
Et
O
2
THF
THF
THF
THF
THF
THF
THF
[
[
d]
e]
[f]
7
8
[e,f]
9
10
20
[
a] Unless indicated otherwise, the following procedure was used:
binol compound (S)-4 from the reaction of (S)-H -binol with
8
Solvent (2 mL, dried) was added under nitrogen to a flask containing
(S)-4 (12.3 mg, 0.025 mmol) and diphenylzinc (66.0 mg, 0.3 mmol). The
solution was stirred at room temperature for 1 h. Valeraldehyde
[
17,18]
morpholinomethanol (Scheme 1).
This compound is a
(0.25 mmol) was then added, and the resulting solution was stirred for
12 h. Aqueous workup and column chromatography on silica gel gave 1-
phenyl-1-pentanol. [b] The products were isolated in 82–89% yield in all
these reactions. [c] The ee values were determined by HPLC-Chiral OD
column. [d] Valeraldehyde was added dropwise over 2 h. [e] (S)-4 was
pretreated with diethylzinc (20 mol%) for 1 h followed by the addition of
diphenylzinc and aldehyde. [f] MeOH (40 mol%) was added after (S)-4
was treated with diphenylzinc or diethylzinc.
Scheme 1. Synthesis of the 3,3’-bismorpholinylmethyl H -binol (S)-4.
8
applying the conditions of entry 4 in Table 1. As summarized
in Table 2, (S)-4 exhibited generally high enantioselectivity
for all the substrates. For the reactions of linear (Table 2,
entries 1–3), a-branched (Table 2, entries 4 and 5) and b-
branched (Table 2, entry 6) aliphatic aldehydes, selectivities
in the range 92–98% ee were attained. Selectivities of 89–
96% ee were found for the reactions of aromatic aldehydes
and an a,b-unsaturated aldehyde (Table 2, entries 6–13). In
all cases, the products were isolated in yields of 75–97%.
Optical rotation measurements showed that the addition to
aliphatic aldehydes gave R alcohols (Table 2, entries 1 and
precursor to a class of bifunctional Lewis acid–base cata-
[
19]
lysts. That is, the dihydroxy groups of (S)-4 can produce a
Lewis acidic center by reacting with a metal alkyl and the 3,3’-
morpholinylmethyl groups of (S)-4 can provide two Lewis
basic nitrogen atoms. We found that (S)-4 in combination with
diethylzinc and Ti(OiPr) catalyzed the addition of phenyl-
4
[
17]
acetylene to aldehydes with high enantioselectivity. Herein
we disclose that this compound also catalyzes the reaction of
diphenylzinc with aldehydes with excellent enantioselectivity,
especially in the case of linear aliphatic aldehydes.
[
20a,b]
5)
and the addition to aromatic aldehydes gave S alcohols
[
18]
[11,20c]
We modified the preparation of (S)-4 and studied its
application in the addition of diphenylzinc to valeraldehyde
under various conditions at room temperature (Table 1). In
solvents such as dichloromethane, toluene, and diethyl ether,
(Table 2, entries 9 and 10).
The relationship between the enantiomeric composition
of the chiral ligand (S)-4 and those of the products of the
addition of diphenylzinc was investigated. Figure 1 displays
the results obtained for the reactions of valeraldehyde and 4-
fluorobenzaldehyde with diphenylzinc in the presence of (S)-
4 at various enantiomeric compositions. Both reactions gave a
linear relationship between the ee value of the chiral ligand
and that of the product. This suggests that the addition of
diphenylzinc to either aliphatic or aromatic aldehydes might
(S)-4 showed very low enantioselectivity (Table 1, entries 1–
3
; 35–39% ee). However, a dramatic increase in enantiose-
lectivity was observed when the reaction was carried out in
THF (Table 1, entry 4; 92% ee). The absolute configuration
of the alcohol product was determined to be R by comparing
[
20]
its optical rotation with that reported in the literature. Slow
addition of the aldehyde did not change the enantioselectivity
significantly (Table 1, entry 5). The use of diethylzinc and/or
methanol as an additive decreased the enantioselectivity
slightly (Table 1, entries 6, 7, and 8). Both increasing and
decreasing the amount of the chiral ligand gave lower ee
values (Table 1, entries 9 and 10).
be catalyzed by a monomeric H -binol catalyst.
8
We conducted an NMR spectroscopic study for the
catalytic addition of diphenylzinc to trimethylacetaldehyde
in the presence of (S)-4. Trimethylacetaldehyde was chosen as
1
the substrate for its simple H NMR spectrum. We first
monitored the interaction of (S)-4 with diphenylzinc in
1
We then used (S)-4 to catalyze the reaction of diphenyl-
zinc with various aliphatic and aromatic aldehydes by
[D ]toluene by using H NMR spectroscopy. Addition of
8
diphenylzinc (1 equiv with respect to (S)-4) gave only partial
2
74
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Angew. Chem. Int. Ed. 2006, 45, 273 –277

Angewandte
Chemie
Table 2: Diphenylzinc addition to various aldehydes catalyzed by (S)-4.
[
a]
[b]
Entry
Aldehyde
Product
t [h] Yield [%]
ee [%]
1
12
87
92
2
3
4
5
6
12
12
8
78
75
96
93
82
93
92
98
98
92
6
16
7
8
9
16
16
16
16
16
90
91
90
92
91
89
89
89
94
91
Figure 1. Relationship between ee values of (S)-4 and those of the
products of addition of diphenylzinc to a) valeraldehyde and b) 4-
fluorobenzaldehyde.
deprotonation of (S)-4. The original singlet at d = 9.99 ppm
for the dihydroxy protons of (S)-4 diminished but multiple
peaks appeared in the range of d = 9.45–9.96 ppm together
with a signal indicating the formation of free benzene. Besides
the signal for free benzene, the aromatic region displayed
additional complicated peaks. This indicates that only one of
the two hydroxy groups of (S)-4 could be deprotonated by
1 equivalent of diphenylzinc and the resulting complexshould
contain a monophenylzinc unit {ZnPh} and a hydroxy group
with a number of isomeric structures. This is understandable
since the multiple Lewis basic sites of (S)-4 could coordinate
to the Lewis acidic {ZnPh} unit in various patterns. In
Scheme 2, compound 5 represents one such [1+1] complex.
When diphenylzinc (1.5 equiv with respect to (S)-4) was
1
1
0
1
1
1
2
3
16
12
97
88
89
96
[
a] Yield of isolated products. [b] Determined by HPLC-chiral column or
GC-chiral column (see the Supporting Information for details).
Scheme 2. Tentative mechanism for the catalytic addition of diphenylzinc.
Angew. Chem. Int. Ed. 2006, 45, 273 –277
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275

Communications
added, all the hydroxy proton signals disappeared and the
aromatic region gave sharp, clean signals at d = 7.68 (d, J =
aldehydes and, especially, is the most enantioselective catalyst
for linear aliphatic aldehydes. Unlike other catalysts devel-
oped for the addition of diphenylzinc—which often require
the addition of a significant amount of diethylzinc with
cooling (or heating) the reaction mixture to ensure high
enantioselectivity—the use of (S)-4 avoids the need for
additive and gives excellent results at room temperature.
7
7
.2 Hz, 2H); 7.55 (s, 1H); 7.48 (d, J = 7.2 Hz, 2H); 7.27 (t, J =
.2 Hz, 2H); 7.20 (t, J = 7.2 Hz, 2H); 7.18–7.10 (m, over-
lapping with the free benzene signal); 6.56 (s, 1H); 6.47 (s,
H); 6.45 ppm (s, 1H). On the basis of gradient double-
1
quantum-filtered (gDQ-COSY) and gradient heteronuclear
single-quantum (gHSQC) correlation spectroscopy experi-
ments, this complexwas characterized as a [2 +3] complex
The one-step synthesis of this ligand from H -binol and the
8
mild asymmetric reaction conditions make this chiral catalyst
practically useful for general synthesis. The NMR study has
also revealed a few interesting mechanistic characteristics of
this catalytic process.
containing two H -binol ligands, three Zn centers, and a total
8
of two phenyl groups on the Zn atoms. The four singlets in the
aromatic region were assigned to the aromatic protons of two
unsymmetrical H -binol ligands. The two doublets, two
8
triplets, and the multiplet were assigned to the two unsym-
Received: September 8, 2005
Published online: November 29, 2005
1
3
metrical phenyl groups on the Zn centers. The C NMR
spectrum of this compound displayed sixdownfield singlets at
d = 160.1, 158.5, 157.1, 156.7, 156.0 and 154.8 ppm: four were
assigned to the aryl carbon atoms bearing the oxygen atom in
the two unsymmetrical ligands and two are due to the ipso
phenyl carbon atom connected to the Zn atom in the {ZnPh}
Keywords: alcohols · aldehydes · asymmetric synthesis ·
.
nucleophilic addition · zinc
[
21]
[1] D. Seebach, A. K. Beck, S. Roggo, A. Wonnacott, Chem. Ber.
units. Compound 6 in Scheme 2 is proposed as a possible
structures for the [2+3] complexgenerated from the reaction
of diphenylzinc with the proposed [1+1] complex 5.
1985, 118, 3673 – 3682.
[
2] R. Noyori, S. Suga, K. Kawai, S. Okada, M. Kitamura, Pure
Appl. Chem. 1988, 60, 1597 – 1606.
Addition of trimethylacetaldehyde to the above [1+1] or
[
3] M. Nakajima, K. Tomioka, K. Koga, Tetrahedron 1993, 49, 9751 –
9758.
[
2+3] complexseparately showed no reaction. This demon-
strates that the phenyl group in the {ZnPh} units of 5 and 6
cannot migrate to the aldehyde. With the addition of up to
[4] J.-T. Wang, X. Fan, X. Feng, Y.-M. Qian, Synthesis 1989, 291 –
92.
5] M. Kaino, K. Ishihara, H. Yamamoto, Bull. Chem. Soc. Jpn.
989, 62, 3736 – 3738.
2
[
1
2 equivalents (with respect to (S)-4) of diphenylzinc in the
1
absence of the aldehyde, the [2+3] complexprobably
dissociated completely to form a compound that may contain
[
[
6] B. Weber, D. Seebach, Tetrahedron 1994, 50, 7473 – 7484.
7] M. Sakai, M. Ueda, N. Miyaura, Angew. Chem. 1998, 110, 3475 –
3477; Angew. Chem. Int. Ed. 1998, 37, 3279 – 3281.
only one H -binol ligand and multiple coordinated {ZnPh }
8
2
1
units. Its H NMR spectrum showed only one singlet at d =
.65 ppm for the aromatic hydrogen atom of the ligand,
[8] a) C. Bolm, M. Kesselgruber, A. Grenz, N. Hermanns, J. P.
Hildebrand, New J. Chem. 2001, 25, 13 – 15; b) J. Rudolph, F.
Schmidt, C. Bolm, Synthesis 2005, 840 – 842; c) C. Bolm, J.
Rudolph, J. Am. Chem. Soc. 2002, 124, 14850 – 14851.
6
indicating the formation of a C -symmetric complexas
2
represented by 7. The conversion of 6 into 7 may involved a
metathesis process between diphenylzinc and the zinc center
in 6 that contains no phenyl group to form the monophenyl-
ated zinc centers in 7. Addition of trimethylacetaldehyde to
this compleximmediately led to phenyl migration to the
[
9] a) J. X. Ji, J. Wu, T. T. L. Au-Yeung, C. W. Yip, R. K. Haynes,
A. S. C. Chan, J. Org. Chem. 2005, 70, 1093 – 1095; b) X. Y. Wu,
X. Y. Liu, G. Zhao, Tetrahedron: Asymmetry 2005, 16, 2299 –
2305.
[10] a) P. I. Dosa, J. C. Ruble, G. C. Fu, J. Org. Chem. 1997, 62, 444 –
445; b) P. I. Dosa, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 445 –
aldehyde. Catalysis by this monomeric H -binol complexis
8
446.
consistent with the observed linear relationship between the
ee value of the ligand and that of the product. The transition
state 8 is proposed for this reaction on the basis of previous
mechanistic work in the area of catalytic asymmetric organo-
[
11] a) W.-S. Huang, L. Pu, J. Org. Chem. 1999, 64, 4222 – 4223;
b) W. S. Huang, L. Pu, Tetrahedron Lett. 2000, 41, 145 – 149.
12] a) C. Bolm, K. Muæiz, Chem. Commun. 1999, 1295 – 126; b) C.
Bolm, N. Hermanns, J. P. Hildebrand, K. Muæiz, Angew. Chem.
2000, 112, 3607 – 3609; Angew. Chem. Int. Ed. 2000, 39, 3465 –
3467; c) C. Bolm, M. Kesselgruber, N. Hermanns, J. P. Hilde-
brand, G. Raabe, Angew. Chem. 2001, 113, 1536 – 1538; Angew.
Chem. Int. Ed. 2001, 40, 1488 – 1490.
[
[
22]
zinc additions. Multiple peaks at d = 4.85–4.25 (tBuCHPh)
and at 0.95–0.60 ppm ((CH ) C) suggest the formation of
3
3
various zinc alkoxide products from the addition of phenyl to
the aldehyde. These zinc alkoxides probably existed as
oligomers or clusters. After complete consumption of diphe-
nylzinc by excess trimethylacetaldehyde, the [2+3] complex
[
13] a) G. Zhao, X.-G. Li, X.-R. Wang, Tetrahedron: Asymmetry
2
2
001, 12, 399 – 403; b) D.-H. Ko, K. H. Kim, D.-C. Ha, Org. Lett.
002, 4, 3759 – 3762.
reappeared. Addition of D O to the reaction mixture
2
[14] M. G. Pizzuti, S. Superchi, Tetrahedron: Asymmetry 2005, 16,
2263 – 2269.
converted the zinc alkoxide products into 2,2-dimethyl-1-
phenyl-1-propanol with two singlets observed at d = 4.01 and
[15] J. M. Betancort, C. Garcia, P. J. Walsh, Synlett 2004, 749 – 760.
[16] M. Fontes, X. Verdaguer, L. Solà, M. A. Pericàs, A. Riera, J. Org.
Chem. 2004, 69, 2532 – 2543.
1
0
.89 ppm in the H NMR spectrum. The ligand (S)-4 was also
regenerated. The mechanism depicted in Scheme 2 on the
basis of the NMR study illustrates our current understanding
of this catalytic process and more work will be conducted.
In summary, (S)-4 allows high enantioselectivity in the
reaction of diphenylzinc with both aliphatic and aromatic
[
[
[
17] L. Liu, L. Pu, Tetrahedron 2004, 60, 7427 – 7430.
18] See the Supporting Information.
19] Selected references on 1,1’-binaphthyl-based bifunctional cata-
lysts: a) M. Kanai, N. Kato, E. Ichikawa, M. Shibasaki, Synlett
2005, 1491 – 1508; b) K. Matsui, S. Takizawa, H. Sasai, J. Am.
2
76
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angewandte
Chemie
Chem. Soc. 2005, 127, 3680 – 3681; c) Y. Hamashima, D. Sawada,
M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 1999, 121, 2641 –
2642; d) J. Casas, C. Nꢀjera, J. M. Sansano, J. M. Saꢀ, Org. Lett.
2002, 4, 2589 – 2592; e) E. F. DiMauro, M. C. Kozlowski, Org.
Lett. 2001, 3, 1641 – 1644.
[
20] a) K. H. Yong, N. J. Taylor, J. M. Chong, Org. Lett. 2002, 4, 3553 –
3556; b) A. M. Hayes, D. J. Morris, G. J. Clarkson, M. Wills, J.
Am. Chem. Soc. 2005, 127, 7318 – 7319; c) G. E. Job, A. Shvets,
W. H. Pirkle, S. Kuwahara, M. Kosaka, Y. Kasai, H. Taji, K.
Fujita, M. Watanabe, N. Harada, J. Chromatogr. A 2004, 1055,
4
1 – 53.
1
3
[
[
21] The C NMR spectrum of diphenylzinc in [D ]toluene showed a
8
singlet at d = 148.4 ppm for the carbon atom connected to the Zn
center.
22] Selected references on the mechanistic studies of the asymmetric
organozinc additions: a) S. Itsuno, J. M. J. Frꢁchet, J. Org. Chem.
1987, 52, 4142 – 4143; b) M. Kitamura, S. Suga, H. Oka, R.
Noyori, J. Am. Chem. Soc. 1998, 120, 9800 – 9809; c) B. Goldfuss,
K. N. Houk, J. Org. Chem. 1998, 63, 8998 – 9006; d) T. Rasmus-
sen, P.-O. Norrby, J. Am. Chem. Soc. 2003, 125, 5130 – 5138; e) J.
Rudolph, C. Bolm, P.-O. Norrby, J. Am. Chem. Soc. 2005, 127,
1548 – 1552; f) A review: L. Pu, H.-B. Yu, Chem. Rev. 2001, 101,
757 – 824.
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