Rhodium/phosphoramidite-catalyzed asymmetric arylation of aldehydes with arylboronic acids

Article abstract of DOI:10.1039/b518311a

Phosphoramidites are effective chiral ligands in the rhodium catalyzed addition of arylboronic acids to aldehydes providing up to 75% enantioselectivity and up to 96% isolated yield. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b518311a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Rhodium/phosphoramidite-catalyzed asymmetric arylation of aldehydes with
arylboronic acids†
a
a
b
a
a
Richard B. C. Jagt, Patrick Y. Toullec, Johannes G. de Vries,* Ben L. Feringa* and Adriaan J. Minnaard*
Received 3rd January 2006, Accepted 21st January 2006
First published as an Advance Article on the web 31st January 2006
DOI: 10.1039/b518311a
Phosphoramidites are effective chiral ligands in the rhodium
catalyzed addition of arylboronic acids to aldehydes pro-
viding up to 75% enantioselectivity and up to 96% isolated
yield.
comprise a low-cost class of ligands that are easily tunable
and therefore highly suitable for a combinatorial approach in
the development of asymmetric catalysts. Herein we report
the efficient rhodium-catalyzed addition of arylboronic acids to
aldehydes with enantioselectivities up to 75% using bidentate
phosphoramidite L2 (Fig. 1).
12
Enantiopure diarylmethanols are key structural elements in a
number of pharmacologically active compounds and therefore
Preliminary studies were carried out with p-chlorobenzaldehyde
(1a), 3 equiv. of phenylboronic acid (2a), and a catalyst prepared in
1
represent important synthetic targets. An attractive route to chiral
situ from 3 mol% Rh(acac)(eth) and 7.5 mol% phosphoramidite
2
enantiopure diarylmethanols is the catalytic asymmetric addition
2
L1. Although a promising 41% enantioselectivity was obtained,
conversion was incomplete under the aqueous conditions com-
monly used for the rhodium-catalyzed conjugate addition of
of aryl organometallic reagents to aldehydes. Diphenylzinc has
been used as a phenyl transfer reagent, but its background reaction
3
with aldehydes makes it difficult to achieve high stereoselectivity.
arylboronic acid (dioxane : H
2
O = 10 : 1, Table 1, entry 1).
This undesired activity could be moderated by the simultaneous
4
5
Interestingly, it was observed that the reaction also proceeded
in non-protic media without water as a co-solvent (entries 2,
4, and 6). In conjugate addition processes of arylboronic acids,
water or alcohol additives have been proven essential to protonate
the rhodium oxa-p-allyl intermediate and thus achieve catalytic
use of diethylzinc. Recently, Bolm et al. reported an excellent
method in which the aryl transfer reagent was generated by mixing
6
arylboronic acids with an excess of diethylzinc. Arylboronic acids
have received increasing attention as arylating reagents because
they are shelf stable, readily available, and compatible with a large
13
7
activity. If work-up with 12.5% aqueous ammonia was omitted,
a mixture of product 3a and a considerable amount of a product
related compound was found. This intermediate was identified as
variety of functional groups. From a practical point of view, the
development of an efficient protocol for their direct addition to
aldehydes would be highly desirable.
14
borate ester 4 (see proposed catalytic cycle in Scheme 1). The
presence of 4 suggests that under these conditions the alcoholate
functionality of species D is able to induce the transmetallation
The addition of arylboronic acids to aromatic aldehydes was ini-
8,9
tially reported by Miyaura in 1998 employing rhodium catalysts.
With MeO–MOP as the chiral ligand, 41% ee was obtained
for the addition of phenylboronic acid to 1-naphthaldehyde.
Subsequent attempts to improve the enantioselectivity of this
Table 1 Solvent variation in the rhodium-catalyzed asymmetric addition
a
10
of arylboronic acids to aldehydes
reaction remained unsuccessful. The development of suitable
chiral ligands for this transformation is still a major goal.
Recently we have demonstrated that rhodium-catalyzed conju-
gate additions of arylboronic acids to enones can be achieved with
high efficiency and excellent enantioselectivities by employing the
11
monodentate phosphoramidite L1 (Fig. 1). Phosphoramidites
b
c
Entry Solvent
Conversion (%)
ee (%)
1
2
3
4
5
6
7
8
Dioxane/H
Dry dioxane
2
O (10 : 1)
79
87
17
26
24
31
45
>99
41
36
44
20
44
42
30
52
Toluene/H
Dry toluene
Tetrahydrofuran/H
Dry tetrahydrofuran
2
O (10 : 1)
Fig. 1 Chiral monodentate (L1) and bidentate (L2) phosphoramidites.
2
O (10 : 1)
a
1,2-Dimethoxyethane/H
2-Propanol
2
O (10 : 1)
Department of Organic and Molecular Inorganic Chemistry, Stratingh
Institute, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The
Netherlands. E-mail: a.j.minnaard@rug.nl, b.l.feringa@rug.nl
a
Reactions were carried out on 0.2 mmol scale in 2 mL of solvent at
b
DSM Research, Life Sciences-Advanced Synthesis & Catalysis, P.O. box
reflux for 4 h with 3 equiv. of phenylboronic acid (2a) in the presence
of a catalyst generated from 3 mol% Rh(acac)(eth) and 7.5 mol% of
phosphoramidite L1. Conversion determined by H-NMR after work-
up with 12.5% aqueous ammonia. Determined by chiral HPLC.
1
8, 6160 MD, Geleen, The Netherlands
2
b
1
†
Electronic supplementary information (ESI) available: Experimental
1
13
c
procedures and H NMR and C NMR spectral data and analytical data
for products 3a–i. See DOI: 10.1039/b518311a
This journal is © The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 773–775 | 773

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a
Table 2 Scope of the rhodium-catalyzed asymmetric addition of arylboronic acids to aldehydes
1
2
b
c,d
Entry
Ar (1)
Ar (2)
Product
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
p-ClC
p-CF
p-PhC
p-MeC
6
H
4
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3d
3i
91
94
93
80
61
93
92
96
89
67
92
60
51
59
60
60
47
53
61
50
52
75
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(R)
(R)
(R)
(R)
3
C
6
H
4
6
H
4
6
H
4
p-MeOC
6
H
4
Ph
Ph
Ph
m-MeOC
o-MeOC
1-Naphthyl
2-Naphthyl
6 4
p-MeC H
2-Naphthyl
Ph
Ph
Ph
Ph
6
H
H
4
3f
6
4
3g
3h
3i
1
1
0
1
a
Reactions were carried out on 0.2 mmol scale in 2 mL of 2-propanol at reflux for 4 h with 3 equiv of boronic acid 2 in the presence of a catalyst
b
generated from 3 mol% Rh(acac)(eth) and 3.5 mol% of bidentate phosphoramidite (S,S)-L2. Isolated yields after column chromatography on silica gel
(
literature values or deduced by analogy (see electronic supplementary information (ESI)†).
2
c
d
heptane:EtOAc − 15 : 1). Determined by chiral HPLC. The absolute configuration of 3a–i was established by comparison of the optical rotation with
3a was obtained in 91% isolated yield with 60% ee (Table 2,
entry 1).
The rhodium-catalyzed arylation of aldehydes is compatible
with a wide range of functional groups (Table 2). As already
8
10
observed by Miyaura and Frost , the reaction is rather sen-
sitive to electronic effects both in aldehyde and arylboronic
acid. Phenylation of aldehydes with electron-withdrawing chloro-
and trifluoromethyl-substituents at the para position gave the
corresponding alcohols 3a and 3b in high yields with 60% and
5
1% enantioselectivity, respectively (entries 1 and 2). In the case
of a para-phenyl group, the product could be isolated in 93% yield
with 59% ee (entry 3). Substrates with electron-donating methoxy-
and methyl-substituents at the para position both provided 60% ee,
but did not proceed to full conversion in 4 h (entries 4 and 5). The
alternative reaction of benzaldehyde with substituted arylboronic
acids did give high yields but showed decreased enantioselectivities
(
entries 6 and 7). A slightly lower ee and reactivity is also observed
for sterically hindered substrates like ortho-methoxy benzaldehyde
entry 9) and 1-naphthyl carboxaldehyde (entry 10). On the
Scheme 1 Proposed mechanism.
(
contrary, 2-naphthyl carboxaldehyde could be phenylated in 92%
isolated yield with an ee of 75% (entry 11).
In summary, catalytic asymmetric synthesis of diaryl-
methanols has been realized with good enantioselectivities (up
to 75%) and high isolated yields (up to 96%) employing a
rhodium/phosphoramidite catalyst system.
step between arylboronic acids and the rhodium center. Due to the
equilibrium between phenylboronic acid and its boroxine trimer,
the water content can not be defined. Although formation of 4
from the product and boronic acid during the reaction can not
be excluded, the 3a : 4 ratio increased during the course of the
reaction, pointing to slow hydrolysis of borate ester 4.
A study of various solvents showed that 2-propanol is the most
suitable solvent for this reaction (compare entries 1–8), increasing
both reactivity and enantioselectivity. Full conversion is obtained
within 4 h resulting in 52% ee. Because of the protic nature of
Acknowledgements
2
-propanol, quenching with aqueous ammonia is not required.
Financial support from DSM, the Ministry of Economic Affairs,
and the Dutch Science Foundation NWO/CW, administered
through the CW/Combichem program, is gratefully acknowl-
edged. We thank Mr. E. P. Schudde and Mrs. T. D. Tiemersma-
Wegman for technical support.
Using these optimized conditions, the parallel synthesis and in situ
screening of a diverse library of phosphoramidites indicated that
bidentate ligand L2 will provide the highest enantioselectivity in
this reaction. Full conversion was reached within 4 h and product
7
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1
14 Borate ester 4 has a characteristic benzhydrilic proton signal in H-
NMR at 6.21 ppm and was further identified by negative ion ESI-
−
7
MS, which gave a specific isotope pattern for C13
H
11ClBO
3
.NH
3
(M–
+
10
35
11
35
NH ): m/z 277.1 (15%, B, Cl), 278.1 (100%, B, Cl), 279.0 (25%,
4
10
37 11 37
B, Cl), 280.0 (25%, B, Cl).
This journal is © The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 773–775 | 775