Boronic acids as versatile aryl sources for the highly enantioselective synthesis of chiral diarylmethanols on multigram scale

Article abstract of DOI:10.1055/s-2004-834887

Chiral diarylmethanols have been synthesized on gram scale in high yields with excellent enantioselectivities using a catalyst with a ferrocenyl oxazoline-based N,O-ligand and mixtures of diethylzinc and arylboronic acid as an aryl source.

Full text of DOI:10.1055/s-2004-834887

8
40
PRACTICAL SYNTHETIC PROCEDURES
Boronic Acids as Versatile Aryl Sources for the Highly Enantioselective
Synthesis of Chiral Diarylmethanols on Multigram Scale
H
J
ighly En
e
antioselecti
n
ve
S
ynthesis
s
of Chiral
D
iar
y
R
lmethanols udolph, Frank Schmidt, Carsten Bolm*
Institut für Organische Chemie, RWTH Aachen, Professor-Pirlet-Strasse 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: Carsten.Bolm@oc.rwth-aachen.de
PSP
Received 16 July 2004
No44
Abstract: Chiral diarylmethanols have been synthesized on gram scale in high yields with excellent enantioselectivities using a catalyst
with a ferrocenyl oxazoline-based N,O-ligand and mixtures of diethylzinc and arylboronic acid as an aryl source.
Key words: diarylmethanols, zinc organyls, catalysis, arylboronic acids
O
B(OH)2
OH
*
1
. ferrocene (10 mol%),
DiMPEG (10 mol%)
H
ZnEt2
2
. work-up
R
R'
R
R'
ferrocene
O
multi-gram scale
up to 96% ee
N
OH
Ph
Fe
Ph
Scheme 1
More and more the pharmaceutical and agricultural indus- tivities in the formation of aryl phenyl methanols 2 have
tries request highly enantioselective syntheses of chiral been achieved, the relatively high catalyst loading, the re-
intermediates and final products due to their attractive bi- quired use of expensive salt-free diphenylzinc, and the re-
1
ological activities and high market values. From a practi- striction to only phenyl transfer remained severe
cal and economical point of view, catalytic methods limitations of this approach.
2
appear most desirable for such syntheses. Enantiomeri-
cally pure diarylmethanols are particularly interesting tar-
get compounds because their structural skeleton can be
found in many pharmaceutically and agriculturally impor-
tant molecules. For example, diarylmethanols are key in-
termediates for the synthesis of antihistaminic agents such
as neobenodine, orphenadrine, or carbinoxamine. More
recently, they have been used for the preparation for 1,1-
O
OH
Ph
1
. ferrocene 3 (10 mol%),
toluene, 10 °C, 12 h
ZnPh2
ZnEt2
2
. work-up
O
R
R
3
1
2
N
OH
up to 99% yield
and 98% ee
diarylalkyl units, which are core structures of antimuscar-
Fe
4
Ph
inics, antidepressants, and endothelin antagonists. Two
Ph
general approaches exist for their synthesis: first, the
3
5
,6
enantioselective reduction of prochiral ketones and sec-
ond, the asymmetric phenyl- or aryl transfer onto aromatic
Scheme 2
7
,8
aldehydes. Despite vast improvements, both methods
lack important criteria for their large-scale application in
industry. For example, the reductive one is only applica-
ble to substrates with significant steric and/or electronic
difference between the two aryl groups. The aryl transfer
Recently, we described the applicability of arylboronic
acids (instead of diphenylzinc) in the aryl transfer reac-
tions and now almost any aryl group can be transferred to
aromatic aldehydes with excellent enantioselectivities.9
Furthermore, the catalyst loading could be reduced in the
phenyl transfer to 1 mol% using polyethylene glycol-
bound ligands or polyglycol ethers as additives. De-
spite these major improvements, further optimizations ap-
peared desirable, in particular when taking into account,
that in large-scale processes the aryl transfer reagent
should be easy to handle, low in cost and allow an aryl
transfer to gain access to diarylmethanols. With respect to
the two former aspects, a first breakthrough was achieved
8
b
protocol reported by us in 2000 (Scheme 2) requires 10
mol% of a catalyst stemming from ferrocene 3 and utilizes
diphenylzinc (in combination with diethylzinc) as aryl
source. Although high yields and excellent enantioselec-
8
f
10
SYNTHESIS 2005, No. 5, pp 0840–0842
x
x
.
x
x
.2
0
0
4
Advanced online publication: 21.10.2004
DOI: 10.1055/s-2004-834887; Art ID: Z13804SS
Georg Thieme Verlag Stuttgart · New York
©

PRACTICAL SYNTHETIC PROCEDURES
Highly Enantioselective Synthesis of Chiral Diarylmethanols
841
by the use of triphenylborane as phenyl source, which al- tive conversions. Interestingly, in the large-scale process
lowed the gram-scale synthesis of arylphenylmethanols. using BPh as aryl source the opposite effect was ob-
3
However, by this method only phenyl groups could be served and a slight decrease in the enantioselective forma-
1
1
transfered. Here, we report the catalytic asymmetric tion of 2c occurred. Since we can exclude solvent and
synthesis of diarylmethanols on a gram-scale using bo- concentration effects, the reasons for these variations in
ronic acids as aryl source. These boron reagents are com- the enantioselectivities still need to be elucidated.
mercially available in large quantities, relatively
inexpensive and easily prepared. Following a modified
protocol in which diphenylzinc was substituted by an aryl-
Noteworthy is also that with the same catalyst both enan-
tiomers of 2b have been prepared with excellent enantio-
meric excesses in high yields simply by using the
boronic acid and a slightly larger amount of diethylzinc
appropriate combination of arylboronic acid and aldehyde
was applied, excellent yields and very high enantioselec-
(
Table 1, entries 2 and 4).
tivities were achieved (Scheme 1 and Table 1). No prob-
lems were encountered in scaling up the reaction, and
in all aspects the results of the 10 mmol scale studies
Furthermore, ferrocene 3 could be recovered in almost
quantitative yield by flash chromatography, and its reuse
in the catalyzed aryl transfer revealed that it had retained
its catalytic activity and enantioselectivity.
were comparable to those previously obtained on the
9
0
.25 mmol scale.
In summary, a protocol for the gram-scale catalytic syn-
thesis of highly enantiomerically enriched diarylmetha-
nols using boronic acids as versatile aryl source has been
reported. The reaction is easy to perform, and the products
are obtained in high yields and excellent enantioselectivi-
ties. Ferrocene 3 serves as catalyst precursor, which can
be recovered almost quantitatively and reused in subse-
quent catalyses. By choosing the right combination of
arylboronic acid and aldehyde both enantiomeric forms of
the product are accessible.
Table 1 Gram Scale Synthesis of Diarylmethanols with Arylboron-
ic Acids as Aryl Sources
a
1. ZnEt2, toluene, 60 °C, 12 h
2
B(OH)2
. ferrocene 3 (10 mol%),
DiMPEG (10 mol%),
toluene, 10 °C, 12 h
O
OH
*
3. work-up
R
R'
a–d 4a: R' = H
b: R' = 4-Me
R
R'
1
2a–c
4
Entry Aldehyde
Arylboronic Product Yield ee
b
(%)c
Acid
(%)
Air sensitive manipulations were carried out under argon using
standard Schlenk techniques. Toluene was distilled from sodium/
1
2
3
4-chlorobenzaldehyde 4a
(R)-2a
93
96
benzophenone ketyl radical. Et O and pentane for column chro-
2
(
1a)
1
13
matograpy were distilled before use. H and C NMR spectra were
recorded on a Varian Gemini 300 spectrometer (300 MHz and 75
MHz respectively) and on a Varian Inova 400 spectrometer (400
MHZ and 100 MHz respectively). HPLC measurements were per-
formed on a Dionex HPLC system (previously Gynkotek) with au-
tosampler Gina 50, UV-detector UVD 170S, degasser DG 503 and
gradient pump M480G. Alternatively the HPLC system HP 1100
from Agilent Technologies was used. As stationary phase chiral
HPLC columns from Chiral Technologies were used.
4-methylbenzaldehyde 4a
(R)-2b 94
96
93
94
(
1b)
2-bromobenzaldehyde 4a
(R)-2c
(S)-2b
99
(
1c)
4
benzaldehyde
4b
95
(
1d)
a
A mixture of 2.4 equiv of arylboronic acid and 7.2 equiv of ZnEt2
Diarylmethanols 2a–d; General Procedure
A well-dried Schlenk flask was charged with arylboronic acid 4 (24
was used in all experiments.
b
After column chromatography.
Enantiomer ratios were determined by HPLC analysis using a chiral
–
1
c
mmol) and dimethylpolyethyleneglycol (M = 2000 g·mol , 2 g, 1
w
mmol) and was sealed with a septum. Freshly distilled toluene (100
column.
mL) was added followed by ZnEt (7.4 mL, 72 mmol). The mixture
2
was heated to 60 °C, stirred for 12 h at this temperature and after-
wards cooled to r.t. In another Schlenk flask, ferrocene 3 (500 mg,
To our delight the previously reported protocol for the
small scale syntheses of diarylmethanols using arylboron-
ic acids worked well on a larger scale, emphasizing the
synthetic value of the method. In terms of the product
yield, the larger-scale process proved highly efficient and
1
mmol) was dissolved in toluene (35 mL) and transferred via sy-
ringe to the first solution. The mixture was stirred for 30 min at r.t.
and then also cooled to 10 °C. Stirring was continued for additional
9
1
0 min at this temperature. A third Schlenk flask was charged with
aldehyde 1 (10 mmol) and dissolved in toluene (35 mL). After cool-
even ortho-substituted diarylmethanol 2c, which had been ing to 10 °C, this solution was transferred via syringe into the other
difficult to prepare in good yield before, was obtained in flask. The reaction was stirred for 12 h at 10 °C. Then the reaction
was carefully quenched with H O (10 mL) and stirred for additional
9
9% yield.
2
1
0 min. Subsequently it was filtered through a pad of Celite and
washed vigorously with CH Cl (400 mL). The organic layer was
In the syntheses of 2a and 2b a slight decrease of enantio-
2
2
selectivity (Dee = 1%) was observed upon scale-up. In washed with AcOH (20% in H O, 250 mL) and H O, dried
2
2
9
contrast, the ee of 2c raised (from 88%) to 93% ee, which (MgSO ), filtered and the solvent removed under reduced pressure.
4
Column chromatography (silica gel, eluents: pentane–Et O, 9:1 to
is a most striking result since ortho-substituted aromatic
aldehydes are usually difficult substrates for stereoselec-
2
8
:2) of the crude product afforded pure 2.
Synthesis 2005, No. 5, 840–842 © Thieme Stuttgart · New York

8
42
J. Rudolph et al.
PRACTICAL SYNTHETIC PROCEDURES
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S)-(4-Methylphenyl)phenylmethanol (2b)13
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4
the general procedure as a pale yellow solid: 1.890 g (95%); 94%
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R
1
H NMR (CDCl , 300 MHz): d = 2.04 (s, 1 H, OH), 2.31 (s, 3 H
3
CH ), 5.76 (s, 1 H, CH), 7.08–7.37 (m, 9 H, H ).
3
arom
1
3
C NMR (CDCl , 75 MHz): d = 21.2 (CH ), 76.2 (CH), 126.6 (2
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3
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(
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(
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Acknowledgment
We thank the Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (DFG) within the SFB 380 and the GK
4
40 for financial support. We also acknowledge Degussa AG, Bay-
er AG, and Crompton Corp. (previously Witco) for the generous do-
nation of chemicals. J. R. thanks Daimler-Chrysler for a
scholarship.
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1
Synthesis 2005, No. 5, 840–842 © Thieme Stuttgart · New York