Asymmetric counterion pair catalysis: An enantioselective Bronsted acid-catalyzed protonation

Article abstract of DOI:10.1002/adsc.200800020

A new asymmetric Bronsted acid-catalyzed cascade reaction involving a 1,4-addition, enantioselective protonation and 1,2-addition has been developed. This organocatalytic cascade not only provides for the first time 3-and 2,3-substituted tetrahydroquinolines and octahydroacridines in good yields with high dia- and enantioselectivities under mild reaction conditions but additionally represents the first example of a chiral Bronsted acid-catalyzed protonation reaction in an organocatalytic domino reaction. Furthermore, the new Bronsted acid-catalyzed hydride-proton-hydride transfer cascade can be applied to prepare new molecular scaffolds with up to three new stereocenters in an efficient one-pot reaction sequence.

Full text of DOI:10.1002/adsc.200800020

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DOI: 10.1002/adsc.200800020
Asymmetric Counterion Pair Catalysis: An Enantioselective
Brønsted Acid-Catalyzed Protonation
Magnus Rueping,a,* Thomas Theissmann,a Sadiya Raja,a and Jan W. Batsa
a
Institute of Organic Chemistry and ChemicalBiool gy, Max-von-Laue Strasse 7, 60438 Frankfurt, Germany
Fax : (+49)-69-798-29248; e-mail: M.Rueping@chemie.uni-frankfurt.de
Received: January 11, 2008; Published online: April 9, 2008
Dedicated to Prof. Dr. Andreas Pfaltz on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A new asymmetric Brønsted acid-cata-
lyzed cascade reaction involving a 1,4-addition,
enantioselective protonation and 1,2-addition has
been developed. This organocatalytic cascade not
only provides for the first time 3- and 2,3-substitut-
ed tetrahydroquinolines and octahydroacridines in
good yields with high dia- and enantioselectivities
under mild reaction conditions but additionally rep-
resents the first example of a chiral Brønsted acid-
catalyzed protonation reaction in an organocatalytic
domino reaction. Furthermore, the new Brønsted
acid-catalyzed hydride-proton-hydride transfer cas-
cade can be applied to prepare new molecular scaf-
folds with up to three new stereocenters in an effi-
cient one-pot reaction sequence.
Within this context, and based on our previous
work on organocatalytic transfer hydrogenations[4] we
recently developed new highly enantioselective partial
reductions of pyridines[5] and quinolines.[6] The corre-
sponding products are not only of great synthetic im-
portance in the preparation of pharmaceuticals, agro-
chemicals, and in materials science, but additionally
many interesting alkaloid natural products contain
these structuralkey eel ments.
With the newly developed enantioselective Brønst-
ed acid-catalyzed transfer hydrogenation we were, for
instance, able to reduce quinolines to the correspond-
ing 2- or 4-substituted tetrahydroquinolines,[6] which
we isolated in good yields and with excellent enantio-
selectivities [Scheme 1, Eq. (1)].
In this first organocatalytic transfer hydrogenation,
the activation of the quinolines is achieved by a cata-
lytic protonation through a chiral Brønsted acid
which subsequently allows a cascade hydrogenation
involving a 1,4-hydride addition, proton transfer and
Keywords: BINOL phosphate; enantioselective iso-
merization; Hantzsch dihydropyridine; organocata-
lytic cascade reaction; transfer hydrogenation
The hydrogenation of unsaturated organic com-
pounds, such as olefins, carbonyls, imines as well as
aromatic and heteroaromatic compounds is one of the
most important and utilized transformations in both
[1]
academia and chemicalindustry.
Due to the con-
stantly increasing number of optically and biologically
active substances asymmetric reductions have become
a centralresearch area in enantioseelctive cataylsis.
So far, most of these enantioselective reductions rely
on chiral transition metal catalysts and highly enantio-
selective hydrogenations of ketones, ketimines and al-
kenes are known.[2] However, most of these metalcat-
alysts failed to give satisfactory results for the asym-
metric hydrogenation of aromatic and heteroaromatic
compounds and examples of efficient and highly se-
lective transformations are rare.[3]
Scheme 1. Brønsted acid-catalyzed enantioselective transfer
hydrogenation of quinolines using Hantzsch dihydropyridine
as the hydride source.
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Figure 1. Key steps in the Brønsted acid catalyzed enantioselective transfer hydrogenation of 2- and 3-substituted quinolines:
a) for 2- and 4-substituted quinolines enantioselectivity is induced by an asymmetric 1,4- or 1,2-hydride addition and b) in
the case of 3-substituted quinolines through a new Brønsted acid catalyzed enantioselective protonation.
1,2 hydride addition to occur (Figure 1a). In the first
Hence our initialinvestigations concentrated on the
step of this enantioselective cascade a protonation of evaluation of various chiral Brønsted acid catalysts
the quinoline 3 by a chiralphosphate cataylst 1 pro- 1a–i in the enantioselective hydride addition-protona-
vides an intermediary chiralion pair A.[4–9] This is tion cascade of the 3-phenyl-substituted quinoline 7a
now activated for the first hydride transfer from (Table 1). From this survey sterically more congested
Hantzsch dihydropyridine 2 to the 4-position of the BINOL-phosphates, such as 1h and 1i emerged as the
quinoline resulting in the formation of an enamine B.
Subsequent Brønsted acid-catalyzed isomerization
yields the iminium C, which is now susceptible for a
second 1,2-hydride transfer to give the desired enan-
tioenriched tetrahydroquinoline and the regenerated
catalyst 1. The mechanistic considerations of the
asymmetric reduction cascade of 2- and 4-substituted
quinolines illustrate that the key step in these reac-
tions consists either of an enantioselective Brønsted
acid-catalyzed 1,2- or 1,4-hydride addition (Fig-
ure 1a). However, in case of 3-substituted quinolines
the stereodetermining step in the cascade reaction
must be different since both the 1,4- and 1,2-hydride
addition of D and F do not provide a stereocenter
(Figure 1b). Hence, the key step of the asymmetric
transfer hydrogenation of 3-substituted quinolines
must be an enantioselective protonation[10] of the en-
amine which after 1,2-hydride addition results in the
3-substituted tetrahydroquinoline 8.
Table 1. ChiralBINOL-phosphates in the enantioseelctive
reduction of 3-substituted quinolines.
Given the importance of tetrahydroquinolines[11] to-
gether with our recently developed transfer hydroge-
nations and cascade reactions we decided to examine
the Brønsted acid-catalyzed enantioselective protona-
tion within reduction of 3-substituted quinolines. This
would not only be the first example of an asymmetric
BINOL-phosphate-catalyzed protonation in general,
but more importantly, it would for the first time pro-
vide direct access to optically active 3-substituted tet-
rahydroquinolines [Scheme 1, Eq. (2)].
[a]
Reactions were performed with quinoline 7a, 2a
(2.4 equiv.) in benzene at 608C with 5 mol% of catalyst
1.
[b]
Determined by HPLC analysis using a chiral stationary
column.
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Table 3. Assessment of catalyst loading and solvent concen-
tration.
best catalysts for the enantioselective protonation
process. The highest enantioselectivities were ob-
tained with the 3,3-triphenylsilyl-substituted H8-
BINOL-phosphate 1i, which provided the 3-phenylte-
trahydroquinoline 8a in 74% ee.
Further examinations focused on the solvent em-
ployed. While the reduction cascade could be per-
formed in all solvents tested, the best selectivities
were achieved in dibutylether (Tabel2, entry 2).
However, the yields were considerable lower as com-
pared to other solvents. The best results with regard
to both selectivity and reactivity were obtained in aro-
matic solvents (Table 2, entries 3–5). This tendency is
in agreement with our earlier observations on Brønst-
ed acid-catalyzed reactions where halogenated and ar-
omatic solvents gave often superior selectivities.[5–8]
Next we examined the catalyst loading and solvent
concentration (Table 3). While a decrease in catalyst
loading resulted in lower enantioselectivities (en-
tries 4 and 5) higher catalyst loadings (entries 1 and 2)
or different solvent concentrations did not show im-
provements. Hence, the best enantioselection was ob-
served if the reaction was carried out with 5 mol% of
BINOL-phosphate 1i in 0.05M solutions of benzene.
In further experiments aiming to improve the enan-
tioselectivities we decided to prepare different dihy-
dropyridines 2a–e and tested them in our Brønsted
acid-catalyzed reduction reaction (Table 4, entries 1–
5). Pleasingly, we found that the reaction proceeded
with better enantiocontrolin alcases and the best se-
lectivities of 8a (81% ee) were obtained if the allyl
ester 2e was employed. Interestingly, further evalua-
tion of the temperature revealed that better enantio-
selectivities were observed at higher (entries 5 and 6)
as compared to lower temperatures (entries 7 and 8).
[a]
Reactions were performed with quinoline 7a, Hantzsch
ester 2a (2.4 equiv.) at 608C.
Determined by HPLC analysis using a chiral stationary
column.
[b]
Table 4. Application of different dihydropyridines 2 and
temperatures in the new Brønsted acid-catalyzed reduction
cascade.
Table 2. Influence of solvent on the enantioselectivity of the
protonation in the reduction cascade.
[a]
Reactions were performed with quinoline 7a, Hantzsch
ester 2 (2.4 equiv.) and 5 mol% 1i.
Determined by HPLC analysis using a chiral stationary
[b]
column.
[a]
Reactions were performed with quinoline 7a, Hantzsch
ester 2a (2.4 equiv) at 608C.
Isolated yields after chromatography.
Determined by HPLC analysis using a chiral stationary
column.
[b]
With the optimized conditions in hand we explored
the scope of the Brønsted acid-catalyzed enantioselec-
tive reduction cascade of various 3-substituted quino-
[c]
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Table 5. Scope of the new Brønsted acid catalyzed enantio-
selective protonation in the reduction cascade.
Figure 2. X-ray crystalstructure of ( À)-camphorsulfonic acid
ammonium salt of 8d.
[a]
Reactions were performed with quinolines 7a–j,
Hantzsch ester 2e (2.4 equiv.) and 5 mol% 1i.
Isolated yield after chromatography.
Determined by HPLC analysis using a chiral stationary
[b]
[c]
column.
Scheme 2. Brønsted acid-catalyzed enantioselective transfer
hydrogenation of 2,3-substituted quinolines.
lines (Table 5). In general, high enantioselectivities
and good isolated yields of several 3-aryl- and hetero-
aryl-substituted tetrahydroquinolines bearing either
electron-donating or electron-withdrawing groups are
observed.
transfer as a key step, the here described reaction cas-
The absolute configuration of the 3-substituted tet- cade involves a new enantioselective Brønsted acid-
rahydroquinoline products was established by an X- catalyzed proton transfer as the enantiodifferentiating
ray crystal structure analysis of the camphorsulfonic step. This is not only the first example of an organo-
acid ammonium salt of 8d (Figure 2).
catalytic protonation in a cascade reaction but more
As a further demonstration of the utility and prac- importantly the new Brønsted acid-catalyzed hydride-
ticability of our newly developed Brønsted acid-cata- proton-hydride transfer cascade can be applied to pre-
lyzed enantioselective reduction cascade we decided pare new molecular scaffolds with up to three new
to additionally explore for the first time the reduction stereocenters in a mild and efficient one-pot reaction
of 2,3-substituted quinolines (Scheme 2). Indeed, sequence.
using the optimized reaction conditions elaborated
before we were able to isolate the octahydroacridine
10 in good yield and with excellent diastereo- and
Experimental Section
enantioselectivities.[12]
In summary, we have developed an unprecedented
enantioselective Brønsted acid-catalyzed transferhy-
drogenation of 3- and 2,3-substituted quinolines
which provides the corresponding tetrahydroquino-
lines or octahydroacridines in good yields and with
high enantioselectivities. In contrast to our earlier de-
veloped Brønsted acid-catalyzed asymmetric transfer
hydrogenations of 2- and 4-substituted quinolines
General Procedure for Asymmetric Reduction of
Quinolines
In a typicalexperiment the quinoilne 7 (0.020 g), catalyst 1
(5 mol%) and Hantzsch dihydropyridine 2 (2.40 equiv.)
were suspended at 0.05M in benzene in a screw-capped vial.
The resulting yellow solution was allowed to stir at 608C for
22–48 h. The solvent was evaporated under vacuum and the
residue was purified by column chromatography on silica
which proceed through an enantioselective hydride gel with toluene as eluent to afford the tetrahydroquinoline.
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The yields and enantiomeric excesses are given in Table 5.
Spectra and analytical data are provided in the supporting
information.
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We gratefully acknowledge Evonik Degussa GmbH as well
as the DFG (Priority Programme Organocatalysis) for finan-
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