Chiral organic contact ion pairs in metal-free catalytic asymmetric allylic substitutions

Article abstract of DOI:10.1021/ja110213t

Chiral contact ion-pair catalysis with particular focus on metal-free processes is gaining in interest. As a result, new perspectives are opened, and highly stereoselective transformations, traditionally performed under metal catalysis, can be realized. H

Full text of DOI:10.1021/ja110213t

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Chiral Organic Contact Ion Pairs in Metal-Free Catalytic
Asymmetric Allylic Substitutions
Magnus Rueping,* Uxue Uria, Ming-Yuan Lin, and Iuliana Atodiresei
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
S Supporting Information
b
ABSTRACT: Chiral contact ion-pair catalysis with parti-
cular focus on metal-free processes is gaining in interest. As a
result, new perspectives are opened, and highly stereoselec-
tive transformations, traditionally performed under metal
catalysis, can be realized. Herein, we report the development
of an unprecedented asymmetric Brønsted acid-catalyzed
allylic alkylation. The concept relies on chiral contact ion-
pair catalysis, in which the chiral organic counteranion of an
allylic carbocation induces high enantioselectivities and
allows access to biologically relevant chromenes in good
yields and with excellent enantioselection.
Figure 1. Potential chiral ion pairs based on carbocations and BINOL-
phosphoric acids and derivatives.
hiral ion-pair catalysis has emerged as a powerful tool for
C
asymmetric organic synthesis. Inspired by nature, research-
ers have designed efficient catalysts and protocols to attain
highest enantioselectivities in a variety of different reactions
involving ion pairing. Today’s strategies mainly involve the use
of cationic phase transfer catalysts,1 chiral anion receptors,2 and
self-assembled supramolecular catalysts,3 as well as Brønsted
acids.4 Depending on the nature of the catalyst the chiral inter-
mediary ion pairs formed consist of either chiral cations1 or chiral
anions.5 In this context, the recently introduced chiral Brønsted
acids,4 in particular BINOL-phosphoric acids and derivatives,6,7
have successfully been employed in the activation of various
substrates through formation of a chiral contact ion pair between
the phosphate/phosphoramide anion X- and cations including
iminium,7 oxocarbenium,8 and episulfonium ions.9 So far, no
catalytic asymmetric process in which an intermediate of type A,
comprising a carbocation and a chiral counteranion, has ever
been described (Figure 1).10-12
Figure 2. Potential chiral Brønsted acid catalyzed asymmetric allylic
substitution.
catalysis, metal-free allylic alkylations involving chiral ion pairs
have remained elusive.
On the basis of our experience in asymmetric ion-pair and
hydrogen-bond catalysis,14,15 we decided to examine a Brønsted
acid-catalyzed enantioselective allylic alkylation reaction, as it
would not only be the first example of such a reaction but would
also open new avenues in asymmetric ion-pair catalysis. When
designing our reaction, we assumed that the alkylation of allylic
alcohol 1 may proceed under chiral Brønsted acid catalysis with
initial formation of a carbocation in the form of a chiral ion pair A
(Figure 2).16 We further anticipated that the activation by the
Brønsted acid would accelerate the subsequent allylic substitu-
tion, providing the desired optically active product 2 with
regeneration of the chiral Brønsted acid catalyst HX. With these
considerations in mind, our attention has been drawn to 2H-1-
benzopyran derivatives 4 (2H-chromenes) which might retro-
synthetically be obtained from allylic alcohol 3, via an intramo-
lecular asymmetric allylic substitution.17
One of the well-established methods for the construction of
carbon-carbon and carbon-heteroatom bonds involving car-
bocations is the allylic alkylation. The development of asym-
metric allylic alkylation reactions13 has played a significant role in
allowing synthetic access to biologically important complex
organic molecules. Yet the field is dominated by metal-catalyzed
processes, which have been extensively studied with a wide
spectrum of metals, including Pd, Mo, Ir, W, Ni, Rh, Ru, Pt,
and Cu complexes. The most common one, palladium, has been
used with considerable success owing to its generally high and
predictable levels of chemo-, regio-, and stereoselectivity. In
contrast, the development of metal-free asymmetric versions
constitutes a significant challenge in organic synthesis, and in
spite of the exciting developments in the field of Brønsted acid
Our interest in this particular class of compounds has also
been raised by the fact that 4 constitutes a family of privileged
Received: November 20, 2010
Published: February 28, 2011
r
2011 American Chemical Society
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Table 1. Catalyst and Temperature Effect on the Asymmetric
Table 2. Substrate Scope of the Organocatalytic Enantio-
selective Allylic Substitution
Allylic Substitutiona
entry
R1
R2
R3
4
yield (%)
eea (%)
1
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
4-Me-Ph
4-MeO-Ph
4-Br-Ph
4-Cl-Ph
4-F-Ph
4b
4c
4d
4e
4f
84
91
80
86
81
95
82
83
87
94
94
88
71
61
93
90
94
94
94
84
90
84
84
92
90
91c
96
93
2
3
entry
Ar
temp (°C) time (h) yield (%) eeb (%)
4
1
2
3
4
5
6
7
8
9
phenyl [H8] (5a)
p-FC6H4 [H8] (5b)
p-MeOC6H4 [H8] (5c)
2,4,6-Me3C6H2 [H8] (5d)
phenyl [H8] (5e)c
phenyl (5f)
0
13
15
16
13
17
20
16
24
19
17
24
24
20
77
87
79
81
94
76
54
82
97
92
80
76
92
56
31
42
46
55
50
16d
12
22
22
73
88
92
5
6b
0
3-Cl-Ph
4-F-Ph
4g
4h
4i
0
7
5-Me
4-MeO
5-Me
5-F
H
0
0
8
4-Cl-Ph
4-Me-Ph
4-Me-Ph
2-thiophen
Ph
9
4j
0
10
11
12
13
14
4k
4l
methyl (5g)
0
phenanthryl (5h)
1-naphthyl (5i)
0
H
4m
4n
4o
0
H
Et
4-Cl-Ph
10 p-ClC6H4 (5j)
0
H
Et
4-Br-Ph
a Enantiomeric excesses were determined by chiral supercritical fluid
chromatography (SFC). b Reaction was performed at -48 °C. c 98% ee
after crystallization.
11 phenyl [H8] (5a)
12 phenyl [H8] (5a)
13e phenyl [H8] (5a)
-48
-78
-78
a Unless otherwise noted, the reactions were performed with 5 mol % of
catalyst (R = CF3) in toluene (0.08 M) at the temperature indicated in
the table. b Enantiomeric excesses were determined by chiral super-
The selectivity proved to be highly dependent on the substit-
uents at the 3,30-positions of the BINOL framework. Among all
catalysts tested, comparable results were obtained with the
BINOL and H8BINOL derivatives bearing phenyl groups at
the 3,30 positions (Table 1, entries 1, 5, 6). Furthermore, a
considerable improvement in the selectivity was obtained by
lowering the temperature (Table 1, entries 12, 13).
c
critical fluid chromatography (SFC). The catalyst 5e with R = C4F9
was used. d The opposite enantiomer was obtained. e Reaction was
performed with 10 mol % of catalyst.
structural motifs,18 being present in many biologically active
natural products which exhibit antioxidant, antiviral, antifungal,
cytotoxic, and anti-inflammatory activities. In addition, closely related
chiral chromans19 are also a class of valuable compounds, e.g. vitamin
E, which is an efficient lipophilic antioxidant, or rhododaurichroma-
nic acid A, which shows potent anti-HIV activity. Therefore, it is
desirable to develop improved methodologies for the synthesis of
chiral chromenes, which could potentially lead to natural products or
their analogues with enhanced pharmacological features.
In order to validate our proposal, we selected phenol 3a as
model substrate and performed a preliminary evaluation of
Brønsted acid nature, catalyst loading and temperature.20 Promis-
ing results (77%, 56% ee) were obtained by employing the highly
acidic N-triflylphosphoramide 5a at 0 °C in toluene.15,21-23 These
results confirmedthat chiralBrønstedacids doindeed promote the
intramolecular allylic alkoxylation in a selective manner and
provided the starting point for the development of an enantiose-
lective catalytic process. Subsequently, the influence of solvent on
the catalytic activity of our system was investigated.20 Although the
reaction proceeded with excellent yields in almost all solvents
tested, the enantioselectivity dropped compared to that of the
reaction performed in toluene. Use of molecular sieves had a
negative effect on both yield and selectivity. Next, in order to
evaluate the influence of the catalyst structure on the reaction
outcome, a small library of chiral N-triflylphosphoramides 5a-j
was examined (Table 1).
With an effective protocol for the enantioselective intramolec-
ular allylic substitution in hands, the scope and generality of the
method with regard to the substrate were examined (Table 2).
The Brønsted acid-catalyzed process exhibits compatibility
with the presence of a wide range of substituted aromatic rings in
the substrate. For example, electron-donating and electron-with-
drawing groups in the para position of the aryl ring conjugated to
the olefin led to the isolation of the corresponding adducts 4b-f
with excellent results (Table 2, entries 1-5). In contrast, when
an electron-withdrawing Cl-group was introduced in the meta
position, no reaction occurred at -78 °C. Nevertheless, an
excellent yield and good enantiomeric excess could be obtained
in a short time by performing the reaction at -48 °C (Table 2,
entry 6). Higher substituted compounds gave similar results,
employing the optimal conditions (Table 2, entries 7-10), as did
a hetereoaromatic ring-bearing substrate (Table 2, entry 11).
Good to high yields and excellent enantioselectivities were also
obtained when the methyl group present in the starting com-
pound was exchanged with the bulkier ethyl group (Table 2,
entries 12-14). These results revealed that catalyst 5a is an
efficient promoter for the metal-free allylic substitution, allowing
entry to a broad range of optically enriched chromenes.
By means of different techniques, e.g. single-crystal X-ray analysis
combined with CD-spectroscopy and theoretical calculations, the
absolute configuration of enantioenriched 4m was assigned as R.20
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system. The HO phenolic group is subsequently deprotonated
by the catalyst, enabling the intramolecular attack of the oxygen
nucleophile and regenerating the effective catalyst. Cation-π
interactions between the substrate and the catalyst are most likely
responsible for the excellent enantioselection observed in the
reaction (Figure 3).
In conclusion, we have developed a new organic ion-pair
catalysis procedure for performing an enantioselective intramo-
lecular allylic substitution catalyzed by a chiral Brønsted acid.
The methodology presented herein has broad scope, providing
the corresponding 2H-chromenes in good yields and with
excellent enantioselectivities. These results highlight the poten-
tial of Brønsted acids in promoting highly stereoselective allylic
reactions via a chiral contact ion pair. The present approach is
particularly attractive as it avoids the use of often toxic metals and
sensitive intermediates. We are thus confident that the concept of
asymmetric ion-pair catalysis in which the chiral information is
efficiently transferred from the Brønsted acid anions to the
product will find broader application in reactions involving
carbocationic intermediates.
’ ASSOCIATED CONTENT
Figure 3. (a) Proposed mechanism for the metal-free, chiral Brønsted
acid-catalyzed allylic alkylation. (b) Simplified stereochemical models of
the contact ion pair B. In the three-dimensional model (bottom, right)
the (-CH2-)4 groups of the catalyst backbone have been omitted for
clarity.
S
Supporting Information. Experimental procedures and
b
full characterization data for all new compounds. EDX spectrum
of compound 5a, crystal structure and CD-spectra of 4m. This
material is available free of charge via the Internet at http://pubs.
acs.org.
Regarding the reaction mechanism, several different pathways
are possible. Although an oxa-6π electrocyclic reaction might be
considered,24 the low temperature (-78 °C) applied in the
reaction allows us not to take into account this pathway.
Furthermore, substrates lacking a vinyl o-quinone methide form
undergo reaction under the given conditions.25 Hence, an allylic
alkylation has been considered. Concerning the mechanism of
the allylic substitution, experiments have been conducted, and
the results support a mechanism with an allylic cation inter-
mediate, over a dynamic kinetic resolution through SN20-type
substitution. Subjection of optically pure substrates (R)- and (S)-
3a (ee > 99%) to the reaction with achiral catalyst allowed
formation of 4a in a racemic form, indicating an intermediate
which lost the chiral information. In addition, optically pure
substrate 3a (ee > 99%) reacted in the presence of chiral catalyst
5a to give the product 4a with 91% ee. If an SN20 reaction would
take place, the enantiomeric excess should be preserved during
the reaction. Hence, the chiral substrate loses its chiral informa-
tion, and the resulting allylic cation intermediate undergoes
substitution reaction to afford the product 4a with the same
enantiomeric excess as in the case of the racemic substrate (ee =
92%). Under the given conditions the products are stable and do
not undergo ring-opening reaction (racemic 4a was isolated
upon treating racemic 4a with 2 equiv of H2O and catalyst 5a).
On the basis of these observations we propose that the
Brønsted acid protonates the allylic alcohol which subsequently
dehydrates to yield a carbocation which is associated with the
phosphoramide anion in a chiral contact ion pair B (Figure 3).
Furthermore, our model favors a carbocation with an anti,anti
configuration that is stabilized through intramolecular π-π
stacking interactions as well as intermolecular electrostatic
interaction with the catalyst. The two ions of the ion pair
orientate in such a way that the positive charge of the cation is
compensated by the negative charge delocalized on the OPNTf
’ AUTHOR INFORMATION
Corresponding Author
Magnus.Rueping@rwth-aachen.de
’ ACKNOWLEDGMENT
Financial support for this project was provided by the European
Research Council. U.U. thanks “Eusko Jaurlaritza -Gobierno
Vasco” for a postdoctoral fellowship.
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