New and improved ligands for highly enantioselective catalytic diphenylzinc additions to aryl aldehydes

Article abstract of DOI:10.1016/S0040-4039(99)02041-9

By introducing electron-withdrawing fluorine atoms to a chiral 1,1'- binaphthyl ligand (R)-1, a new catalyst (S)-5d has been obtained which shows improved catalytic properties for the asymmetric diphenylzinc addition to aldehydes. This new ligand allows the synthesis of chiral diarylcarbinols with high enantioselectivity in shorter reaction time under simple reaction conditions.

Full text of DOI:10.1016/S0040-4039(99)02041-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 145–149
New and improved ligands for highly enantioselective catalytic
diphenylzinc additions to aryl aldehydes
∗
Wei-Sheng Huang and Lin Pu
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901, USA
Received 30 September 1999; revised 27 October 1999; accepted 28 October 1999
Abstract
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By introducing electron-withdrawing fluorine atoms to a chiral 1,1 -binaphthyl ligand (R)-1, a new catalyst
(S)-5d has been obtained which shows improved catalytic properties for the asymmetric diphenylzinc addition to
aldehydes. This new ligand allows the synthesis of chiral diarylcarbinols with high enantioselectivity in shorter
reaction time under simple reaction conditions. © 1999 Elsevier Science Ltd. All rights reserved.
Chiral diarylcarbinols are synthetically useful in the preparation of some biologically active
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molecules. In recent years, Corey and coworkers have developed a synthesis of chiral diarylcarbinols
by a catalytic asymmetric reduction of prochiral ketones containing electronically and/or sterically very
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different diaryl groups.
Although the asymmetric addition of an aryl reagent to an aryl aldehyde
seems more suitable for chiral induction because of the large steric and electronic differences between
an aryl group and a hydrogen on an aldehyde substrate, no highly enantioselective catalysts are
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obtained for this reaction until recently.
In 1994, Weber and Seebach found that an in situ generated
(
RO) Ti–Ph reagent can add to aryl aldehydes in the presence of a chiral titanium catalyst with high
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enantioselectivity. Recently, we have achieved the first highly enantioselective diphenylzinc addition to
aryl and alkyl aldehydes by using (R)-1 as the catalyst ligand.11 Shortly after, Bolm and co-workers also
reported a chiral ferrocenyl hydroxy oxazoline compound 2 to catalyze the addition of diphenylzinc to
certain aldehydes with good enantioselectivity.12
∗
Corresponding author.
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040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02041-9
tetl 15969

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Compound (R)-1 in combination with 2 equiv. of diethylzinc catalyzes the diphenylzinc addition to
-chlorobenzaldehyde with 94% ee and to cinnamaldehyde with 83% ee.11 The reaction with cinnamal-
4
dehyde requires the use of methanol as an additive in a refluxing methylene chloride solution. In order
to gain further information about this chiral ligand and also to improve this catalytic process, we have
modified (R)-1 mainly by tuning its electronic effects and have discovered a new ligand with improved
catalytic properties. Herein, these results are reported.
During our study of the catalytic diphenylzinc addition, we have realized that the main challenge
is to overcome the uncatalyzed reaction of diphenylzinc with aldehydes.11 This requires the chiral
catalyst-mediated reaction to be much faster than the background reaction in order to achieve efficient
chiral induction. A strategy to increase the catalytic activity of ligand (R)-1 is therefore undertaken
by introduction of electron-withdrawing substituents in order to increase the Lewis acidity of the
catalytically active zinc centers that are generated in situ from the reaction of (R)-1 with 2 equiv. of
diethylzinc.
A series of new chiral ligands (S)-5a–e where multiple electron-withdrawing fluorine atoms are
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introduced to the 3,3 -aryl groups were synthesized by the Suzuki coupling of (S)-3 with aryl
bromides 4a–e followed by acidic hydrolysis (Scheme 1). Treatment of (S)-5b with bromine specifically
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introduced bromine atoms to the 6,6 -positions of the binaphthyl unit to generate ligand (S)-6. Ligands
(S)-5a–d and (S)-6 were used to catalyze the diphenylzinc addition to cinnamaldehyde without using
the methanol additive. The catalytic properties of these new ligands are compared with (R)-1, and the
results are summarized in Table 1. In these reactions, each ligand was first treated with 2 equiv. of
diethylzinc in methylene chloride and then a 20 mol% of the in situ generated zinc complex was used to
catalyze the diphenylzinc addition to cinnamaldehyde. As shown in Table 1, with the introduction of the
electron-withdrawing substituents, all these new ligands exhibit much better enantioselectivity than (R)-
1. Without addition of methanol, (R)-1 gave only 50% ee. However, under the same conditions, ligand
(S)-5d showed up to 87% ee. This compound has the highest enantioselectivity among all the ligands
tested. No improvement was observed with the addition of methanol when (S)-5d was used.
A six-membered ring transition state as shown in 7 is proposed to account for the electronic effects of
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these ligands. In transition state 7, introduction of an electron-withdrawing substituent X onto the 3-
aryl substituent of the binaphthyl unit should reduce the electron density of the etheral oxygen atom
coordinated to the catalytically active zinc center, thus increasing the Lewis acidity of the zinc and
further activating the aldehyde. A more active catalyst makes the chiral ligand-controlled reaction more
competitive than the uncatalyzed reaction, further enhancing the enantioselectivity. Compound (S)-5d
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has two fluorine atoms on each of the 3,3 -aryl substituents and exhibits much higher enantioselectivity
than the more electron rich ligand (R)-1. However, ligand (S)-5c though with three fluorine atoms on
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each of the 3,3 -aryl substituents does not show further enhancement in enantioselectivity over (S)-
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5d. In the 3,3 -aryl groups of (S)-5c, there is a fluorine atom ortho to an alkoxy group. This fluorine

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Scheme 1. Synthesis of the chiral binaphthyl ligands (S)-5a–e and (S)-6
Table 1
Reaction of cinnamaldehyde with diphenylzinc in the presence of the chiral ligandsa
atom may be able to participate in the coordination to a zinc center with the adjacent alkoxy group
and thus perturb the catalyst structure. Contrarily, the ortho methyl groups in (S)-5b may provide a
better steric control for the diphenylzinc addition than (S)-5a and give a higher enantioselectivity. In
transition state 7, when a strong electron-withdrawing substituent Y is introduced to the position 6, it
may reduce the diphenylzinc coordination to the 2-oxygen atom and thus disfavor the chiral ligand-
0
controlled diphenylzinc addition. Therefore, the bromine atoms at the 6,6 -positions of the binaphthyl
unit in (S)-6 lead to reduced enantioselectivity from (S)-5b.

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The high enantioselectivity of ligand (S)-5d for the addition of diphenylzinc with cinnamaldehyde has
prompted us to examine its use for the reaction of various aryl aldehydes in order to prepare optically
active diarylcarbinols. These results are summarized in Table 2. Unlike (R)-1 which requires longer
reaction time, in some cases ≤0°C and also very different reaction conditions for different substrates
in order to achieve high enantioselectivity, (S)-5d can catalyze the reaction of various aryl aldehydes
with diphenylzinc at room temperature in methylene chloride in 5 h with high enantioselectivity. For
example, the reaction of 2-naphthaldehyde catalyzed by (R)-1 took 4 days at −10°C with incomplete
conversion and 66% isolated yield. However, in the presence of (S)-5d, this reaction was completed in 5
h at room temperature with 90% isolated yield (entry 4). We have also studied the use of (S)-5d and (S)-
5e to catalyze the diphenylzinc addition to 3-pyridinecarboxaldehyde. Ligand (S)-5e where the hexyloxy
groups of (S)-5d were replaced with the smaller methoxy groups gave a lower ee (entry 6) than (S)-5d
(
entry 5). When the nitrogen of 3-pyridinecarboxaldehyde was protected with triethylborane, its reaction
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with diphenylzinc in the presence of (S)-5d gave 86% ee and 89% yield (entry 7).
Table 2
Synthesis of chiral diarylcarbinols by the diphenylzinc addition to aryl aldehydes catalyzed by (S)-5da
In summary, through a systematic tuning of the electronic properties of ligand (R)-1, we have obtained
a new catalyst (S)-5d with improved catalytic properties for the asymmetric diphenylzinc additions. The
fluorine substituents in (S)-5d can increase the Lewis acidity of the corresponding zinc complex, leading
to higher catalytic activity and better catalyst control over the uncatalyzed background reaction. This new
ligand allows the synthesis of chiral diarylcarbinols with high enantioselectivity in shorter reaction time
under simple reaction conditions.

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Acknowledgements
We thank, for support of this work, the donors of the Petroleum Research Fund — administered by the
American Chemical Society and the Jeffress Memorial Trust.
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