The first general, efficient and highly enantioselective reduction of quinoxalines and quinoxalinones

Article abstract of DOI:10.1002/chem.200902907

(Chemical Equation Presented) Simple yet efficient: A series of diverse substituted tetrahydroquinoxalines and dihydroquinoxalinones have been synthesized for the first time in a highly enantioselective fashion (see scheme). Using this metalfree hydrogena

Full text of DOI:10.1002/chem.200902907

DOI: 10.1002/chem.200902907
The First General, Efficient and Highly Enantioselective Reduction of
Quinoxalines and Quinoxalinones
Magnus Rueping,* Francisco Tato, and Fenja. R. Schoepke[a]
Tetrahydroquinoxalines and dihydroquinoxalinones pos-
sess important biological and pharmacological properties.[1]
By 1947 various tetrahydroquinoxalines had already been
synthesized to examine their antimalarial activity.[2] Since
then interest in the tetrahydroquinoxalines and dihydroqui-
noxalinones has significantly increased.
of the unnatural diasteromer may be toxic, leucovorine is
still generally used as a racemate due to the lack of alterna-
tive synthetic methods. Despite the great importance of the
tetahydroquinoxalines and dihydroquinoxalinones there are
only very few enantioselective synthetic routes. To date effi-
cient synthetic methods include catalytic reactions[9] or
solid-phase synthesis.[10] However, they generally require
multiple reaction steps and the introduction of a chiral
amino alcohol or a corresponding amino acid.[11] With par-
ticular emphasis on economic and ecologically valuable pro-
cesses, asymmetric hydrogenation represents a highly effi-
cient and atom-economic approach.[12]
General, catalytic, enantioselective hydrogenations of qui-
noxalines and quinoxalinones are not known, yet they repre-
sent the simplest method for synthesizing optically active
tetrahydroquinoxalines and dihydroquinoxalinones. To date
only the catalytic enantioselective reduction of 2-methylchi-
noxaline has been described.[13,14] However, for instance in
the case of DC-SIGN, as is often the case with tetrahydro-
quinoxalinones, the ones with aromatic substituents in the 2-
position are more biologically active.
Therefore, we decided to examine a general, catalytic,
enantioselective reduction of both quinoxalines and quinox-
alinones. In particular, we wanted to concentrate on aryl-
substituted derivatives, as these have been shown to be es-
pecially biologically active. As our initial work towards a
metal-catalyzed, asymmetric reduction did not deliver the
desired results with regard to high reactivity and selectivity,
we decided to also examine metal-free transfer hydrogena-
tions.[15,16] Here, the initial experiments showed that various
Brønsted acids such as diphenylphosphate are able to cata-
lyze the transfer hydrogenation of quinoxaline 1a to the cor-
responding 2-phenyl-tetrahydroquinoxaline 3a in the pres-
ence of the Hantzsch dihydropyridine 2a as a hydride
source. Further, it was shown that the concentration of the
solvent is a determining reaction parameter, especially with
regard to the reactivity: The reactivity continuously increas-
es with increasing solvent concentration.
They function as potent inhibitors of glycoproteins; in-
cluding DC-SIGN,[3] which facilitates the spread of viruses
such as HIV, Hepatitis C, or Ebola; or CETP, which in its
inhibited state counteracts atherosclerosis.[4] Furthermore,
they have been reported to open calcium channels;[5] or
serve as highly selective antagonists for diverse receptors,
for example Kinin B1, which is associated with inflammation
and pain in septicemia.[6] An example of a promising dihy-
droquinoxalinone is GW420867X, a non-nucleoside HIV-1
reverse transcriptase inhibitor, which is currently in clinical
trials.[7] Furthermore, due to the similarity in their structure,
tetrahydroquinoxalines are used as models for tetrahydrofol-
ic acids (coenzyme F) and their derivatives, for example,
leucovorine.[8] The latter serves as a “rescue agent” in che-
motherapy together with methotrexate. Even though it is
only the natural diastereomer of leucovorine that acts as a
competitive inhibitor, and the possibility that long-term use
[a] Prof. Dr. M. Rueping, Dr. F. Tato, F. R. Schoepke
Institute of Organic Chemisty, RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-809-2127
E-mail: magnus.rueping@rwth-aachen.de
The following studies concentrated on the development of
the first asymmetric variant in which the chiral phosphoric
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902907.
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Chem. Eur. J. 2010, 16, 2688 – 2691

COMMUNICATION
Table 2. Effect of various Hantzsch esters on the transfer hydrogenation
of quinoxalines.
acid diesters 4a–4 f (Table 1) were employed.[17] Here only
minimal differences in the reactivity were seen, while the
enantioselectivity varied greatly. The best results with
Entry[a]
HEH
R
Conv. [%][b]
e.r.[c]
1
2
3
4
2a
2b
2c
2d
ethyl
allyl
tert-butyl
benzyl
94
85
45
89
95:5
90:10
92:8
92:8
Table 1. Survey of chiral Brønsted acid catalysts for the enantioselective
reduction of quinoxalines.
[a] Reaction conditions: 1a, 2a (2.4 equiv) and 4e (5 mol%), 508C,
chloroform (0.5m), 24 h. [b] Conversions were determined by 1H NMR
spectroscopy of the crude reaction mixture. [c] Enantiomeric excess was
determined by HPLC using Chiralcel OD-H.
quinoxalines (Table 3). It was thereby shown that diverse 2-
aryl-tetrahydroquinoxalines 3a–3n with electron-withdraw-
ing as well as electron-donating substituents can be isolated
in good yields and with excellent enantioselectivities (up to
98% ee).[18]
Interestingly, the metal-free hydrogenation is also compat-
ible with various halogenation patterns, enabling easy varia-
tions of both, the aryl substituent as well as the tetrahydro-
quinoxaline core. The absolute configuration of the product
was established by means of an X-ray structure analysis of
compound 3e (Figure 1).
Entry[a]
Catalyst
Ar
Conv. [%][b]
e.r.[c]
1
4a
4a
4b
4c
4c
4d
4e
4e
4 f
1-naphthyl
1-naphthyl
2-naphthyl
9-phenanthryl
9-phenanthryl
Ph3Si, [H]8
anthracenyl
anthracenyl
2,4,6-(iPr)3-phenyl
98
98
97
98
99
66
100
100
100
78:22
64:36
55:45
82:18
80:20
À53:47
95:5
2[d]
3
4
5[d]
6
7
8[e]
9[e]
94:6
94:6
[a] Reaction conditions: 1a, 2a (2.4 equiv) and 4 (10 mol%), 408C,
chloroform (0.5m), 24 h. [b] Conversions were determined by 1H NMR
spectroscopy of the crude reaction mixture. [c] Enantiomeric excess was
determined by HPLC using Chiralcel OD-H. [d] In toluene (0.5m) at
608C. [e] 5 mol% of catalyst was used.
regard to conversion and enantioselectivities were observed
with Brønsted acid catalyst 4e in chloroform, which on full
conversion resulted in the formation of 2-phenyl-tetrahydro-
quinoxalines with an excellent enantiomeric ratio of 95:5
e.r. (Table 1, entry 7). The use of 4 f gave a similar result
(Table 1, entry 9), whereas the other phosphoric acid die-
sters resulted in considerably lower selectivities (Table 1, en-
tries 1–6).
Figure 1. Molecular structure of (R)-7-Chloro-2-phenyl-1,2,3,4-tetrahy-
droquinoxaline 3e.
While the steric demand in the 3,3’-position of the
BINOL skeleton has a significant impact on the asymmetric
induction, the steric demand of the hydride source plays a
lesser role. Thus, the best result was achieved with Hantzsch
diethyl ester 2a (Table 2, entry 1), whereas the other
Hantzsch esters 2b–2d showed reduced enantioselectivities
(Table 2, entries 2–4).
Additionally, the variation of the temperature had negligi-
ble impact on the transfer hydrogenations that we exam-
ined. Over a temperature range from room temperature to
508C, both the reactivities and the enantioselectivities
changed only minimally. Thus, we conducted the reductions
at 358C. Using the optimized reaction conditions we tested
the substrate scope of this first organocatalytic, enantiose-
lective reduction by employing various 2-aryl- and hetroaryl-
During the further course of our studies we decided to
extend our transfer hydrogenation procedure to incorporate
quinoxalinones, as to date no asymmetric reduction for
these important substrates has been developed. To our de-
light, the reaction proceeds with high enantioselectivities. In
contrast to the reduction of the benzopyrazines, in this in-
stance the reactions were carried out in THF at 508C. This
change was necessary due to the lower solubility of the qui-
noxalinones (Table 4). Thus, for the first time various dihy-
droquinoxalinones 5a–e were obtained with excellent enan-
tioselectivities (up to 98% ee).
In summary, we have developed the first highly enantiose-
lective reduction of both quinoxalines as well as quinoxali-
nones. The new method can effectively be applied in the
transformation of diverse aryl-substituted quinoxalines and
Chem. Eur. J. 2010, 16, 2688 – 2691
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www.chemeurj.org
2689

M. Rueping et al.
Table 3. Scope of the asymmetric Brønsted acid catalyzed reduction of
Table 4. Scope of the asymmetric Brønsted acid catalysed reduction of
quinoxalines 1.
quinoxalinones 5.
[a] Reaction conditions: 5a, 2a (2.4 equiv) and 4 (10 mol%), 508C, THF
(0.2m), 24 h. [b] Isolated yields after column chromatography. Enantio-
meric excess was determined by HPLC using Chiralcel OD-H.
Acknowledgements
We gratefully acknowledge financial support by DFG (Schwerpunktprog-
ramm Organokatalyse), the Fonds der Chemischen Industrie for a sti-
pend given to F.R.S., and the Ministerio de Educacion y Ciencia, Spain
for a postdoctoral fellowship for F.T.
Keywords: Brønsted
acid
·
Hantzsch
ester
·
organocatalysis · pyrazine · pyridine · transfer hydrogenation
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4 (10 mol%), 358C,
chloroform (0.5m), 24 h. [b] Isolated yields after column chromatography.
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Enantioselective Reduction of Quinoxalines and Quinoxalinones
COMMUNICATION
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Received: October 21, 2009
Published online: February 5, 2010
Chem. Eur. J. 2010, 16, 2688 – 2691
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2691