Cooperative iron-bronsted acid catalysis: Enantioselective hydrogenation of quinoxalines and 2h-1,4-benzoxazines

Article abstract of DOI:10.1002/chem.201204236

The financial support from the state of Mecklenburg-Vorpommern and the Bundesministerium fur Bildung und Forschung (BMBF) is gratefully acknowledged. S.F. is thankful for the financial support of the Evonik Stiftung. We thank Dr. W. Baumann, Dr. C. Fische

Full text of DOI:10.1002/chem.201204236

COMMUNICATION
DOI: 10.1002/chem.201204236
Cooperative Iron–Brønsted Acid Catalysis: Enantioselective Hydrogenation
of Quinoxalines and 2H-1,4-Benzoxazines
Steffen Fleischer,[a] Shaolin Zhou,[b] Svenja Werkmeister,[a] Kathrin Junge,[a] and
Matthias Beller*[a]
Chiral six-membered nitrogen heterocycles, such as substi-
tuted piperazines, morpholines and piperidines, are found in
commercialised highly potent antibacterial agent[10] and ob-
scurinervine and its related compounds are examples for
naturally accruing alkaloids.[11]
many naturally occurring alkaloids as well as in phar
ACHUTGTNRNEUGmN aHCATUNGTRNEcNUGN eu-
A
E
With the growing importance of such chiral compounds in
the life science industries, the development of efficient enan-
tioselective methodologies continues to be interesting for or-
ganic chemistry and catalysis. Clearly, beside different multi-
step methods to synthesise chiral tetrahydroquinoxalines[12]
and dihydro-benzoxazines[13] the most direct and atom-eco-
nomic approach represents the enantioselective hydrogena-
tion of quinoxalines and benzoxazines. Notably, virtually all
of the known catalysts for the latter enantioselective hydro-
bioactive compounds.[1] The biological and pharmacological
properties of their aryl-fused analogues tetrahydroquinoxa-
line and dihydro-2H-benzoxazine have been known for a
long time. As early as 1947 various tetrahydroquinoxalines
have already been synthesised to explore antimalarial activi-
ty,[2] whereas the antituberculouses properties of dihydro-
benzoxazines have been shown only ten years later.[3]
Since then, interest in tetrahydroquinoxalines and dihy-
dro-2H-benzoxazines has in-
creased significantly and today
optically active 2-substituted
1,2,3,4-tetrahydroquinoxalines[4]
and 3-substituted 3,4-dihydro-
2H-1,4-benzoxazines[5] consti-
tute interesting building blocks
in the drug discovery process
and are an important motif of
many naturally occurring alka-
loids (Figure 1). More specifi-
cally, the chiral 1,2,3,4-tetrahy-
droquinoxaline A is a promis-
ing M2 acetylcholine receptor
inhibitor,[6] whereas B has been
pursued as a potent V2 recep-
tor antagonist.[7] In addition, C
is known to represent an active
cholesteryl ester transfer pro-
Figure 1. Selection of bioactive compounds and alkaloids containing tetrahydroquinoxaline and dihydro-2H-
1,4-benzoxazine frameworks.
tein inhibitor[8] and the chiral
1,4-benzoxazine D is a promis-
ing candidate in atherosclerosis
treatment.[9] Levofloxacin is a
genation are based on noble metals such as Ru, Rh and
Ir.[14,15] Owing to the comparably high price of these pre-
cious metals and their limited availability the search for
[a] S. Fleischer, S. Werkmeister, Dr. K. Junge, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
more economical and environmentally friendly catalysts
based on Zn, Cu and Fe offers particular attractive op-
tions.[16–18] However, despite obvious advantages enantiose-
lective hydrogenations based on these metals remain an un-
derrepresented field. To the best of our knowledge, no re-
ports of enantioselective hydrogenations of quinoxalines
and benzoxazines by using non-noble metal catalysts are
known.
E-mail: matthias.beller@catalysis.de
[b] Dr. S. Zhou
College of Chemistry, Central China Normal University
Luoyu Road, No. 152, 430079 Wuhan (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204236.
Chem. Eur. J. 2013, 19, 4997 – 5003
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4997

Only recently, non-noble metal catalysts were reported
for the homogeneous enantioselective hydrogenation of ke-
tones and simple imines. For example, the hydrogenation of
C=O bonds based on Cu catalysts was reported by Shimizu
et al.[18a–d] and our group.[18e] In 2008, Morris et al.[19] report-
ed the first enantioselective hydrogenation of acetophenone
applying an Fe-based complex with a tetradentate PNNP
ligand. Furthermore, Berkessel and co-workers[20] used phos-
phoramidate ligands to form chiral Fe complexes for the
enantioselective hydrogenation of acetophenone.
Scheme 2. Hydrogenation of compound 1a with the Fe-based catalyst 4.
TMS=trimethylsilyl.
An alternative but highly selective approach has been re-
ported by Rueping et al., List et al., MacMillan et al., and
Antilla and co-workers, which use chiral Brønsted acids as
organocatalysts for the enantioselective reduction of C=N
bonds.[21] Notably, the research group of Rueping applied
this methodology in the highly enantioselective reduction of
2-aryl-quinoxalines and 3-aryl-benzoxazines by using chiral
Brønsted acids as organocatalysts.[21a,i] Unfortunately, in all
these reactions stoichiometric amounts of expensive 2,6-di-
Due to the importance of chiral 1,2,3,4-tetrahydroqui-
noxalines our following studies concentrated on expanding
this protocol towards an enantioselective version. As chiral
1,1’-binaphthalene-2,2’-diol (binol) phosphoric acid esters
showed high selectivity in the enantioselective reduction of
C=N bonds by using Hanztsch ester as reducing agent, we
thought that the proper choice of the chiral phosphoric acid
esters 3 will control the enantioselectivity of the hydrogena-
tion. Although the latter acid 3 has to activate specifically
substrate 1a, the former Fe-based hydrogenation catalyst 4
has to react with the activated intermediate to perform the
cooperative hydrogenation.
methyl-1,4-dihydropyridine-3,5-dicarboxylates
(Hanztsch
esters) have to be applied as the hydrogen source and the
formation of pyridines as co-products limited the application
of this methodology (Scheme 1).
To our delight, the combina-
tion of catalyst 4 with various
chiral 3,3’-biaryl-1,1’-binaphth-
yl-2,2’-diyl
hydrogen
phos-
phates (3a–3e), two H8-bi-
naphthyl analogous (3g and
3h) and (R)-2,2’-diphenyl-3,3’-
biphenanthryl-4,4’-diyl
phos-
phate (VAPOL hydrogenphos-
phate, 3 f) created active cata-
lysts for the enantioselective
hydrogenation of 1a (Table 1,
entries 1–8). The different sub-
stituents at the 3- and 3’-posi-
Scheme 1. a) Organocatalytic reduction and b) cooperative enantioselective Fe-catalysed hydrogenation of qui-
noxalines 1 and 2H-1,4-benzoxazines 5.
Based on our recent work on the cooperative iron-cata-
lysed hydrogenation of imines we report here a highly selec-
tive asymmetric hydrogenation of various nitrogen heterocy-
cles (Scheme 1).[22] The combination of a molecularly de-
fined achiral Fe-hydrogenation catalyst with a chiral Brønst-
ed acid allows for the enantioselective reduction of various
2-substituted quinoxalines and 3-substituted 1,4-benzoxa-
zines with environmentally friendly hydrogen gas to form
the corresponding chiral tetrahydroquinoxalines and dihy-
dro-2H-1,4-benzoxazines in high yields up to 97% with ex-
cellent enantiomeric ratios (e.r.) up to 97:3.
tion of 3a–3e as well as 3g and 3h had only a little impact
on the product yield (67–99%), whereas a significant influ-
ence on the enantiomeric ratios was observed (54:46 to
95:5). Without any substituents at the 3- and 3’-position,
only low enantioselectivity occurred (Table 1, entry 2). Steri-
cally demanding aryl substituents led to an increased enan-
tioselectivity (Table 1, entries 1, 4, and 5), whereas the best
results were obtained by using bi- and tricyclic moieties
(Table 1, entries 3, 7 and 8). Notably, chiral Brønsted acids
with axial R configuration yielded product 2a with S config-
uration and vice versa (Table 1, entries 1–8).
For our initial studies the hydrogenation of 2-phenylqui-
noxaline (1a) was chosen as a benchmark reaction. The
achiral Fe complex 4, which was synthesised according to
the work of Knçlker and co-workers,[23] was able to hydro-
genate both C=N double bonds of 1a and racemic 2a was
obtained with 51% yield under non-optimised conditions
(Scheme 2).[24] Notably, this reaction represents the first ex-
ample of an Fe-catalysed hydrogenation of quinoxalines.
Under the model conditions the Brønsted acid 3c in com-
bination with the Fe complex 4 allows for the smooth hydro-
genation of the heterocyclic core giving 2-phenyl-1,2,3,4-tet-
rahydroquinoxaline (2a) in high yield of 87% and an excel-
lent enantiomeric ratio of 95:5 (Table 1, entry 3). Important
to note, the level of enantioselectivity observed with an iron
precursor rivals those of the most efficient precious-metal-
based hydrogenations as well as organocatalytic transfer hy-
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Cooperative Iron–Brønsted Acid Catalysis
COMMUNICATION
and with new stirring bars.[26] Furthermore,
control experiments without any catalyst
(Table 1, entry 14) and without Fe complex
4 (Table 1, entry 15) did not show any prod-
uct formation, which confirms the catalytic
effect of the Fe species.
Table 1. Enantioselective Fe-catalysed hydrogenation of 1a in the presence of various
chiral Brønsted acids 3.[a]
During the further course of our studies
we decided to extend our enantioselective
hydrogenation procedure to incorporate
benzoxazines to form biologically important
chiral 3,4-dihydro-2H-1,4-benzoxazines. To
our delight, also this reactions proceed with
good enantioselectivity (Table 2). However,
in contrast to the hydrogenation of quinoxa-
lines, the best enantiomeric ratio of 83:17
was observed by applying 3a as chiral
Brønsted acid (Table 2, entry 1).
Once suitable catalyst systems were iden-
tified, the scope and limitations of our novel
iron-catalysed enantioselective hydrogena-
tion by using different 2-substituted qui-
noxalines as substrates were explored. A va-
riety of quinoxalines with aromatic, hetero-
aromatic, cyclic and aliphatic substituents at
the heteroaromatic core and different sub-
stituents at the 6- and 7-position were hy-
drogenated smoothly with high yields up to
97% and good to excellent enantiomeric
ratios up to 97:3 (Table 3, entries 1–14).
Both electron-donating and electron-with-
drawing substituents on the aromatic rings
at meta or para position had little impact on
the hydrogenation activity and high enantio-
selectivity is observed for meta- and para-
substituted 2-aryl-quinoxalines (Table 3, en-
tries 1–8). Gratifyingly, substituents at the 6-
and 7-position are tolerated (Table 3,
Entry Brønsted catalyst 3 ([mol%]) T [8C] p [bar] Yield[b] [%]
e.r.
(S):(R)-2a[c]
1
2
3
4
5
6
7
8
9
10
11
12
13[d]
14[e]
15[f]
(R)-3a (2)
(R)-3b (2)
(R)-3c (2)
(S)-3d (2)
(S)-3e (2)
(R)-3 f (2)
(R)-3g (2)
(R)-3h (2)
(R)-3c (2)
(R)-3c (2)
(R)-3c (2)
(R)-3c (1)
(R)-3c (1)
–
40
40
40
40
40
40
40
40
40
40
60
60
60
60
60
20
20
20
20
20
20
20
20
5
40
5
5
5
5
99
74
87
85
75
67
75
81
81
80
98
98
93
–
86:14
54:46
95:5
26:74
19:81
89:11
92:8
90:10
95:5
95:5
94:6
94:6
94:6
n.d.
(R)-3c (1)
5
–
n.d.
[a] Reaction conditions: 1a (0.5 mmol), Brønsted acid 3 (1–2 mol%), Fe catalyst 4
(5 mol%), toluene (1 mL), H2 (5–40 bar) at 40–608C for 24 h. [b] The yield was deter-
mined by GC analysis by using hexadecane as an internal standard. [c] The e.r. value
was determined by HPLC on a chiral stationary phase. [d] Complex 4 (3 mol%).
[e] Reaction was performed without 3 and 4. [f] Reaction was performed without 4.
Table 2. Evaluation of the chiral Brønsted acids 3 for the enantioselec-
drogenations by using stoichiometric amounts of Hanztsch
esters.[25]
tive hydrogenation of benzoxazines.[a]
Next, the influence of critical reaction parameters such as
temperature, pressure and catalyst loading were investigated
(Table 1, entries 9–15). A study of the dependence on the
hydrogen pressure showed that it has little influence on
both yield and enantioselectivity. Hence, lowering the hy-
drogen pressure from 40 to 5 bar did not lower the yield and
the enantiomeric ratio stays as high as 95:5 (Table 1, entry 9
and 10). Increasing the temperature to 608C at 5 bar hydro-
gen pressure led to full conversion and 2a was obtained in
98% yield with an enantiomeric ratio of 94:6 (Table 1,
entry 11). We were pleased to see that under these condi-
tions the reaction of 1a was efficiently catalysed at low cata-
lyst loading of 1 and 3 mol% for 3c and 4, respectively
(Table 1, entry 13). In order to ensure that the observed cat-
alyst activity was not caused by other metal impurities pres-
ent, we performed each reaction in brand new glass vials
Entry
Brønsted catalyst 3 ([mol%])
e.r.
(S):(R)-2a[b]
1
2
3
4
5
(R)-3a (2)
(R)-3b (2)
(R)-3c (2)
(S)-3d (2)
(S)-3e (2)
87:13
52:48
66:33
45:55
47:53
[a] Reaction conditions: 5a (0.5 mmol), Brønsted acid 3 (2 mol%), Fe
catalyst 4 (5 mol%), toluene (1 mL), H2 (5 bar) at 608C for 24 h. [b] The
e.r. value was determined by HPLC on a chiral stationary phase.
Chem. Eur. J. 2013, 19, 4997 – 5003
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M. Beller et al.
Table 3. Cooperative Fe-catalysed enantioselective hydrogenation of qui-
noxalines 1 and benzoxazines 5.
Table 3. (Continued)
Entry Imine
Product Yield[b] [%] e.r. (S)-2/(S)-6[d]
14
15
2n
6a
94
90
83:17
87:13
Entry Imine
1
Product Yield[b] [%] e.r. (S)-2/(S)-6[d]
2a
2b
90
82
94:6
92:8
16
17
18
19
6b
6c
6d
6e
74
67
76
69
84:16
80:20
80:20
79:21
2
3
4
5
6
7
2c
2d
2e
2 f
2g
95
91
91
91
83
91:9
92:8
94:6
94:6
95:5
[a] General reaction conditions for quinoxalines: 1 (0.5 mmol), Brønsted
acid 3c (1 mol%), Fe catalyst 4 (3 mol%), toluene (1 mL), H2 (5 bar) at
608C for 24 h; for benzoxazines:
(2 mol%), Fe catalyst 4 (5 mol%), toluene (1 mL), H2 (5 bar) at 608C
for 24 h. [b] Yield of the isolated product after column chromatography
[c] The e.r. value was determined by HPLC on a chiral stationary phase.
[d] Complex 4 (3 mol%).
5 (0.5 mmol), Brønsted acid 3a
entry 9) and 2-(naphthalen-2-yl)quinoxaline (1j) was re-
duced with excellent yield and enantiomeric ratio (Table 3,
entry 10).
As heteroaromatic compounds play an important role in
the life science industries we draw our attention towards
heteroaromatic substituents. 2-(Thiophen-3-yl)quinoxaline
(1k) and 2-(furan-2-yl)quinoxaline (1l) were again hydro-
genated with excellent yields and good to high enantiomeric
ratios (Table 3, entries 11 and 12).
We were also interested, if alkyl-substituted quinoxalines
can be applied with our catalyst system, too. In contrast to
organocatalytic systems applying Hanztsch esters as reduc-
ing agents the reduction of alkyl-substituted substrates is
achieved with high yield and good enantioselectivity
(Table 3, entries 13 and 14).[21]
Furthermore, different benzoxazines can be reduced with
the Fe complex 4 and 3a as chiral Brønsted acid. As expect-
ed, the sense of the absolute configuration of product 6 is
again S, which shows that the configuration is not influenced
by the heteroatom X. For 6a–6e enantiomeric ratios up to
87:13 are obtained, which is slightly lower compared to the
hydrogenation of 1 with 3c (Table 3, entries 15–19).
Finally, we wanted to improve the step economy for the
synthesis of chiral quinoxalines. Here, our aim was to use
commercially available starting materials and to synthesise
8
2h
2i
91
80
97
94:6
88:13
97:3
9
10
2j
11
12
13
2k
2l
96
95
94
94:6
80:20
88:12
2m
5000
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Cooperative Iron–Brønsted Acid Catalysis
COMMUNICATION
chiral quinoxalines in a one-step procedure, which has not
been reported so far. In order to do so, we combined com-
mercially available glyoxal and 1,2-phenylenediamine, which
form quinoxaline in a condensation reaction. The resulting
quinoxaline might then be enantioselectively reduced in situ
to the corresponding chiral tetrahydroquinoxaline. In this
reductive amination procedure water is the only byproduct
formed.
Following our concept, 1,2-phenylenediamine (7) and phe-
nylglyoxal (8) were reacted in toluene in the presence of six
different iron-based hydrogenation catalysts 4a–4d, 5a and
5b and 3c as the chiral Brønsted acid (Scheme 3). To our
delight all iron complexes 4a–4d as well as 5a and 5b yield-
studies towards the extension of this strategy to other syn-
thetically interesting compounds are in progress in our labo-
ratory.
Experimental Section
Typical procedure for the enantioselective hydrogenation of quinoxalines
1: Under an argon atmosphere (glovebox), a brand new glass vial was
charged with 1 (0.5 mmol), (R)-3c (0.005 mol), complex 4 (0.015 mmol),
toluene (1.5 mL) and a magnetic stirring bar. The glass vial was capped
with a septum equipped with a syringe. The vial was placed in the alloy
plate, which was then placed to the predried autoclave. Once sealed, the
autoclave was purged three times with hydrogen, then pressurised to
5 bar and heated at 608C for 24 h. After reaction, the autoclave was
cooled to room temperature, depressurised and the reaction mixture
was transferred to a flask. The solvent was evaporated under reduced
pressure and the residue was purified by column chromatography on
silica gel (eluent: hexane/ethyl acetate 10:1) to give the corresponding
compound 2, which was then analysed by NMR spectroscopy, HRMS
and chiral HPLC to determine the e.r. value.
Typical procedure for the enantioselective hydrogenation of benzoxa-
zines 5: Under an argon atmosphere (glovebox), a brand new glass
vial was charged with 5 (0.5 mmol), (R)-3a (0.01 mol), complex 4
(0.025 mmol), toluene (1.5 mL) and a magnetic stirring bar. The glass
vial was capped with a septum equipped with a syringe. The vial was
placed in the alloy plate, which was then placed to the predried auto-
clave. Once sealed, the autoclave was purged three times with hydro-
gen, then pressurised to 5 bar and heated at 608C for 24 h. After reac-
tion, the autoclave was cooled to room temperature, depressurised and
the reaction mixture was transferred to a flask. The solvent was evapo-
rated under reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: hexane/ethyl acetate 10:1) to
give the corresponding compound 6, which was then analysed by
NMR spectroscopy, HRMS and chiral HPLC to determine the e.r. value.
Scheme 3. Reductive amination procedure to produce 2a.
ed the chiral tetrahydroquinoxaline 2a in good yield and
high enantioselectivity. Complex 4a showed the best results
giving 2a in 75% yield and an enantiomeric ratio of 95:5.
Remarkably, no drop in enantioselectivity was observed
compared to the hydrogenation of the isolated quinoxaline
3a (Table 1, entry 3).
Acknowledgements
The financial support from the state of Mecklenburg-Vorpommern and
the Bundesministerium fꢀr Bildung und Forschung (BMBF) is gratefully
acknowledged. S.F. is thankful for the financial support of the Evonik
Stiftung. We thank Dr. W. Baumann, Dr. C. Fischer, S. Buchholz, S.
Schareina, A. Koch, and S. Smyczek (all at the LIKAT) for their excel-
lent technical and analytical support.
Comparison of our iron-based system to well established
Ru, Rh and Ir hydrogenation catalysts in combination with
chiral Brøn
of Shvo, [{RuACHTUNGTRENNUNG(p-cymene)I2}2] and [{RhACHTUNGTERN(NUNG cod)Cl}2] (cod=cy-
clooctadiene) in combination with the chiral Brønsted acid
3c in the reductive amination of 1,2-phenylenediamine (7)
and phenylglyoxal (8) (see the Supporting Information).
However, the catalyst of Shvo yielded 2a only as a racemic
ACHTUNGTRENNUNG
sted acids[27] proved some activity of the catalysts
Keywords: asymmetric catalysis
·
enantioselectivity
·
hydrogenation · iron · organocatalysis · quinoxalines
mixture. Notably, applying [{Ru
used by Zhou et al. in the enantioselective reduction of qui-
noxalines,[14h] or [{Rh
(cod)Cl}2], in both cases 2a was ob-
ACHTUGNERTN(NUGN p-cymene)I2}2], which was
AHCTUNGTRENNUNG
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enantioselective hydrogenation of quinoxalines and benzox-
azines without precious metal catalysts and chiral ligands.
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acids allows for smooth hydrogenation with enantiomeric
ratios up to 97:3. Employing hydrogen gas as the reductant
makes this transformation an ideal atom-economical pro-
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Chem. Eur. J. 2013, 19, 4997 – 5003

Cooperative Iron–Brønsted Acid Catalysis
COMMUNICATION
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[26] Stirring bars were used brand new and used stirring bars were exclu-
sively applied for noble-metal-free reactions and before use cleaned
with Aqua regia, water and acetone.
[27] For more details, see the Supporting Information.
[25] Selected examples of enantiomeric ratios for the enantioselective
hydrogenation of 1a by using precious metals: reference [14e]:
Received: November 27, 2012
Published online: March 5, 2013
Chem. Eur. J. 2013, 19, 4997 – 5003
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5003