Catalytic enantioselective arylation of aldehydes: Boronic acids as a suitable source of transferable aryl groups

Article abstract of DOI:10.1039/b501485a

The catalytic enantioselective arylation of several aldehydes using boronic acids as the source of transferable aryl groups is described; the reaction is found to proceed in excellent yields and high enantioselectivities (up to 97% ee) in the presence of a chiral amino alcohol. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b501485a

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Catalytic enantioselective arylation of aldehydes: boronic acids as a
suitable source of transferable aryl groups{
Antonio L. Braga,* Diogo S. Lu¨dtke, Fabr´ıcio Vargas and Marcio W. Paixa˜o
Received (in Bloomington, IN, USA) 28th January 2005, Accepted 17th March 2005
First published as an Advance Article on the web 1st April 2005
DOI: 10.1039/b501485a
by treatment with diiodoalkane and potassium carbonate in
boiling acetonitrile.
The catalytic enantioselective arylation of several aldehydes
using boronic acids as the source of transferable aryl groups is
described; the reaction is found to proceed in excellent yields
and high enantioselectivities (up to 97% ee) in the presence of a
chiral amino alcohol.
It is noteworthy that the structural features of amino alcohol 2
are easily changed at any step of the synthesis, since modifications
can be introduced at several different positions of the molecule.
For instance, these changes can be made in the R group, which
corresponds to the amino acid residue, both R1 groups, derived
from the addition of the Grignard reagent, or the size of the
nitrogen heterocycle.
Over the past decades, great progress has been made in the
catalytic asymmetric addition of organozinc reagents to aldehydes
using chiral amino alcohols as ligands, and products with excellent
enantiomeric excesses have been achieved with all types of
substrates.1 More recently, the enantioselective arylation of
aldehydes in the presence of a chiral ligand has received special
attention since it gives access to chiral diarylmethanols, important
precursors for pharmacologically and biologically important
compounds.2 Since the pioneering work of Fu,3 several reports
concerning the preparation of chiral diarylmethanols by arylzinc
addition to aldehydes have been published.4 One interesting
approach to the synthesis of such compounds has been recently
introduced by Bolm and co-workers.5 It consists of using aryl
boronic acids as the source of the transferable aryl group. This new
methodology offers interesting advantages over the use of Ph2Zn
itself, or the most widely used Ph2Zn–Et2Zn mixture, because: (1)
it allows the easy preparation of several substituted arylzinc
reagents and therefore the synthesis of a wide range of substituted
chiral diarylmethanols and (2) phenylboronic acids offer a cheaper
alternative to the expensive diphenyl zinc.6
With this sterically and electronically varied set of enantiopure
amino alcohols in hand, we first examined the efficiency of these
ligands as chiral catalysts in the enantioselective arylation of
p-tolualdehyde with phenylboronic acid. The results of this study
are depicted in Table 1.
All ligands were employed in the enantioselective arylation
reaction and furnished the desired product in high yields with
different levels of enantiocontrol. Initially we decided to examine
the influence of the R1 group while the R position was held
constant as the aromatic ring of the side chain of phenylalanine
(Table 1, Entries 1–5). Variations in the R1 group have shown that
it plays an import role in the enantioselectivity of the reaction and
the best result was achieved with the catalyst with R1 5 Et (ee 92%,
Entry 3). Steric factors appear to play the dominant role in
determining enantioselectivity in this series of ligands. The size of
the aza-ring is also important for the outcome of the reaction and
a great decrease in the ee was observed when catalyst 2e, with a
smaller pyrrolidine ring was used instead of 2b (compare Entries 3
and 8). Reaction temperature does not seem to have a significant
impact on the enantioselectivity, which conveniently simplifies the
experimental procedure. The influence of the solvent was also
examined. The use of toluene is crucial for a high enantioselec-
tivity, since lower ees were obtained by employing hexane and a
mixture of toluene–hexane (Entries 3, 6 and 7). This fact is
probably due to a poor solubility of the reactive zinc species
resulting from the boron–zinc exchange reaction.
Since the catalytic asymmetric aryl transfer reaction to carbonyl
compounds using boronic acids as the aryl source has not been
extensively studied,5,7 the search for efficient chiral ligands to
generate high enantioselectivities in such reactions still remains an
important challenge in this area.
In connection with our current interests in the asymmetric
addition of organozinc reagents to aldehydes,8 we describe herein
our efforts toward the synthesis of optically active diarylmethanols,
employing chiral b-amino alcohols as catalysts.9 The modular
structure of this type of ligands has attracted our attention since
they are easily available in a few synthetic steps with a very flexible
strategy.
Extending our studies to other ligands with variations at the R
position, we could gratifyingly observe that ligand 2f (R 5 i-Pr,
The chiral ligands were rapidly synthesized in a two step
synthesis as described in Scheme 1. First, commercially available
amino ester hydrochlorides were subjected to a double Grignard
addition or hydride reduction to produce the corresponding amino
alcohols, which were further converted to the aza-ring derivatives
{ Electronic supplementary information (ESI) available: experimental
section. See http://www.rsc.org/suppdata/cc/b5/b501485a/
*albraga@quimica.ufsm.br
Scheme 1 General synthesis of ligands 2. Reagents and conditions: (i)
5 equiv. R1MgBr, THF, rt; (ii) diiodoalkane, K2CO3, CH3CN, reflux.
2512 | Chem. Commun., 2005, 2512–2514
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that steric hindrance does not play an important role in
determining the degree of enantioselection. For instance, ortho-
substituted benzaldehydes underwent aryl transfer with the same
level of enantioselectivity as their para analogues (compare Entries
1 vs. 2 and Entries 3 vs. 4).
Table 1 Catalytic arylation of p-tolualdehyde with phenylboronic
acida
In order to examine if different aryl groups could be transferred
to aldehydes with the same stereoselectivity, giving access to a
range of substituted diaryl carbinols, the aryl transfer reactions of
some substituted aryl boronic acids with benzaldehyde were
studied and, to our delight, excellent yields and enantiomeric
excesses were obtained (Entries 8–10). For example, the aryl
transfer reaction from 4-methoxyphenyl boronic acid to benzalde-
hyde occurred in 94% ee (Entry 9).
Yieldb eec,d
Entry Ligand
R
R1
n
Solvent
(%)
(%)
1
2a
2a
2b
2c
2d
2b
2b
2e
2f
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
Ph
Et
Me
H
Et
Et
Et
1
1
1
1
1
1
1
0
1
1
1
Toluene
Toluene
Toluene
Toluene
Toluene
93
88
97
95
88
70 (R)
70 (R)
92 (R)
62 (R)
07 (R)
70 (R)
50 (R)
65 (R)
97 (R)
91 (R)
91 (R)
2e
3
4
5
6f
7
Toluene–hexane 95
This is one of the most interesting features of the methodology
employed herein since both enantiomers of a given product can be
easily prepared in excellent yields and high enantiomeric excesses
with the same catalyst, just by appropriate choice of both reaction
partners; aryl boronic acid and aldehyde.
Hexane
Toluene
Toluene
Toluene
Toluene
64
95
97
98
88
8
9
i-Pr Et
s-Bu Et
i-Bu Et
10
11
2g
2h
a
Reactions were performed on a 0.5 mmol scale with PhB(OH)2
(2.4 equiv.) and Et2Zn (7.2 equiv.) in toluene (first at 60 uC for 12 h,
In summary, we have described the asymmetric arylation of
aldehydes in the presence of a catalytic amount of chiral amino
alcohol. The reactive arylzinc species is generated in situ from a
boron–zinc exchange10 instead of employing the more expensive
diphenylzinc and its reaction with aldehydes gives access to several
chiral diaryl methanols in high yields and ees. The selectivities are
comparable to the best ligand known for this reaction. Studies
dealing with the mechanism of the reaction and application of this
catalyst system in other asymmetric catalytic reactions are
currently in progress in our laboratory.
b
then at room temperature for 24 h).
corresponding product. Enantiomeric excesses were determined by
Isolated yield of the
c
d
chiral HPLC on
a
Chiralcel1 OD column.
Configuration
e
determined by comparison with literature data.4e,5 Reaction was
f
carried out at 0 uC. A 1:1 mixture of toluene and hexane was used
as solvent.
R1 5 Et, n 5 1) had the best performance, delivering product 4 in
a high yield and in an excellent ee of 97% (Table 1, Entry 9).
With ligand 2f identified as the most effective, next we examined
the scope of our system in reactions with several aromatic
aldehydes with diverse electronic and steric properties. Reactions
with o- and p-tolualdehyde underwent smooth aryl addition in
very high enantiomeric excesses and with nearly quantitative yields
(Table 2, Entries 1 and 2). When o- and p-methoxybenzaldehyde
were employed, decreased enantiomeric excesses of the corre-
sponding products were achieved (Entries 3 and 4). On the other
hand, when electron-withdrawing groups were present in the
aldehyde, the enantioselectivity was also lower than when
p-tolualdehyde was used. With regard to steric effects, we observed
The authors gratefully acknowledge CAPES, CNPq and
FAPERGS for financial support. CAPES is also acknowledged
for providing PhD fellowships to D.S.L. and M.W.P and CNPq
for a PhD fellowship to F.V. We are also grateful to Prof. L. A.
Wessjohann, Dr J. Schmidt, C. Neuhaus and A. Schneider (IPB,
Germany) for HPLC and HRMS analysis.
Antonio L. Braga,* Diogo S. Lu¨dtke, Fabr´ıcio Vargas and
Marcio W. Paixa˜o
Departamento de Qu´ımica, Universidade Federal de Santa Maria,
97105-900, Santa Maria, RS, Brazil. E-mail: albraga@quimica.ufsm.br;
Fax: +55-55-220-8998; Tel: +55-55-220-8761
Table 2 Catalytic arylation of aldehydes with aryl boronic acids
Notes and references
1 For comprehensive reviews of organozinc additions to carbonyl
compounds, see: (a) R. Noyori and M. Kitamura, Angew. Chem., Int.
Ed. Engl., 1991, 30, 49–69; (b) K. Soai and S. Niwa, Chem. Rev., 1992,
92, 833–856; (c) R. Noyori, Asymmetric Catalysis in Organic Synthesis,
Wiley, New York, 1994, ch. 5; (d) L. Pu and H.-B. Yu, Chem. Rev.,
2001, 101, 757–824.
Yielda eeb,c
Entry Ar1
Ar2
(%)
(%)
2 (a) K. Meguro, M. Aizawa, T. Sohda, Y. Kawamatsu and A. Nagaoka,
Chem. Pharm. Bull., 1985, 33, 3787–3797; (b) F. Toda, K. Tanaka and
K. Koshiro, Tetrahedron: Asymmetry, 1991, 2, 873–874; (c) S. Stanchev,
R. Rakovska, N. Berova and G. Snatzke, Tetrahedron: Asymmetry,
1995, 6, 183–198; (d) M. Botta, V. Summa, F. Corelli, G. Di Pietro and
P. Lombardi, Tetrahedron: Asymmetry, 1996, 7, 1263–1266; (e) for a
recent review on catalyzed asymmetric arylation reactions, see: C. Bolm,
J. P. Hildebrand, K. Mun˜iz and N. Hermanns, Angew. Chem. Int. Ed.,
2001, 40, 3284–3308.
3 P. I. Dosa, J. C. Ruble and G. C. Fu, J. Org. Chem., 1997, 62, 444–445.
4 (a) W.-S. Huang, Q.-S. Hu and L. Pu, J. Org. Chem., 1999, 64,
7940–7956; (b) C. Bolm and K. Mun˜iz, Chem. Commun., 1999,
1295–1296; (c) C. Bolm, N. Hermanns, J. P. Hildebrand and K. Mun˜iz,
Angew. Chem. Int. Ed., 2000, 39, 3465–3467; (d) J. Rudolph,
N. Hermanns and C. Bolm, J. Org. Chem., 2004, 69, 3997–4000; (e)
1
2
3
4
5
6
7
8
9
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
4-Methylphenyl
4-Methylphenyl (4a)
2-Methylphenyl (4b)
4-Methoxyphenyl (4c) 97
2-Methoxyphenyl (4d) 98
4-Chlorophenyl (4e)
2-Chlorophenyl (4f)
2-Bromophenyl (4g)
Phenyl (4a)
97
93
97 (R)
97 (R)
81 (R)
81 (R)
89 (R)
88 (R)
89 (R)
88 (S)
94 (S)
94 (S)
87
85
91
98
98
97
4-Methoxyphenyl Phenyl (4c)
4-Chlorophenyl Phenyl (4d)
10
a
b
Isolated yield of the corresponding product.
excesses were determined by chiral HPLC.
determined by comparison with literature data.4e,5
Enantiomeric
Configuration
c
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