Asymmetric Homogeneous Hydrogenation of 2-Pyridones

Article abstract of DOI:10.1055/s-0034-1378703

An asymmetric homogeneous hydrogenation of 2(1H)-pyridones has been developed, using a ruthenium complex bearing two chiral N-heterocyclic carbene (NHC) ligands. To the best of our knowledge, the presented reaction is the first example of a homogeneous asymmetric conversion of 2-pyridones into the corresponding enantioenriched 2-piperidones.

Full text of DOI:10.1055/s-0034-1378703

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1557–1562
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Asymmetric Homogeneous Hydrogenation of 2-Pyridones
Jędrzej Wysockia,b
Christoph Schlepphorsta
Frank Glorius*a
[Ru(NHC)2], H2
solvent
R
R
N
O
N
O
a Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Münster, Corrensstr. 40, 48149 Münster, Germany
glorius@uni-muenster.de
b NRW Graduate School of Chemistry, Wilhelm-Klemm-Str. 10,
48149 Münster, Germany
yields up to 99%
e.r. 94:6 and lower
N
N
Dedicated to Peter Vollhardt for all the inspiration he has given the
chemistry world
NHC
Received: 10.03.2015
Accepted: 15.04.2015
Published online: 11.05.2015
DOI: 10.1055/s-0034-1378703; Art ID: st-2015-b0171-l
It is, however, of great importance to note that the
asymmetric hydrogenation of heterocyclic compounds re-
mains a very challenging process despite the progress
achieved to date in this area. The major obstacle concerns
the need to overcome the energy barrier imposed by aro-
maticity, which has generally resulted in the requirement
for elevated pressures and reaction temperatures. Unfortu-
nately, these may negatively affect the stereochemical out-
come. Some elements, especially nitrogen and sulfur, tend
to poison the catalysts and therefore completely shut down
the process. Another problem that could cause a lowering
of the enantioselectivity is the weaker coordination ability
of simple unsaturated cyclic compounds, which in the ab-
sence of additional coordinating functional groups can ulti-
mately hamper the face recognition of the starting material
by the catalyst.
Growing demand for more efficient and selective meth-
ods to access valuable enantioenriched intermediates and
fine chemicals has triggered the development of a wide
range of interesting and impressive homogeneous catalytic
systems for the asymmetric hydrogenation of various het-
erocyclic compounds. Since 1987, scientists have witnessed
a great expansion of this area which reflected in a number
of efficient methods for the asymmetric homogeneous hy-
drogenation of quinolines,2 isoquinolines,3 quinazolines,4
quinoxalines,5 pyridines,6 indoles/pyrroles,7 phenanthro-
lines,8 (benzo)thiophenes,9 (benzo)furans,10 indolizines,11
naphthyridines,12 and even carbocycles.13 By contrast, how-
ever, in the case of 2-pyridones, to the best of our knowl-
edge, only heterogeneous hydrogenation reactions have
been disclosed to date, with no examples offering asym-
metric induction. Depending on the structure of the start-
ing compounds, Pd/C and PtO2 have been among the most
often employed catalysts.14
Abstract An asymmetric homogeneous hydrogenation of 2(1H)-pyri-
dones has been developed, using a ruthenium complex bearing two
chiral N-heterocyclic carbene (NHC) ligands. To the best of our knowl-
edge, the presented reaction is the first example of a homogeneous
asymmetric conversion of 2-pyridones into the corresponding enantio-
enriched 2-piperidones.
Key words asymmetric catalysis, hydrogenation, NHC, piperidone,
pyridone
Over the last couple of decades the asymmetric homo-
geneous hydrogenation of heterocyclic compounds has be-
come a subject of growing interest for organic chemists.1
Conventional synthetic methods towards analogous enan-
tioenriched saturated compounds possess several draw-
backs which limit their attractiveness, particularly during
the scaling up of the process. In most cases they require
multi-step pathways including protecting group chemistry,
complicated work-up and purification methods, and often
superstoichiometric quantities of expensive chiral reagents.
These entail lower overall yields and the production of sig-
nificant amounts of chemical waste, contrary to the princi-
ples of green chemistry.
Asymmetric hydrogenation, on the other hand, makes
use of a relatively environmentally benign and comparably
very inexpensive reagent – molecular hydrogen (H2). In
combination with chiral metal-based catalysts at low load-
ings, asymmetric homogeneous hydrogenation comprises
an elegant and attractive method for accessing enantioen-
riched multisubstituted cyclic or aliphatic compounds of
high biological relevance. As such, it can allow for the short-
ening and simplification of synthetic routes towards com-
plex enantioenriched molecules.
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We have recently reported on the development and ap-
plication of a ruthenium(II)-based complex bearing chiral
N-heterocyclic carbene (NHC) ligands [Ru(SINpEt)2]. This
privileged system has been successfully applied in the
asymmetric hydrogenation reactions of a wide range of het-
erocycles: quinoxalines,13b benzofurans,10f–g (benzo)thio-
phenes,9c flavones and chromones,15 indolizines,11 and fu-
rans.10h Inspired by these studies, we sought to investigate
whether it would be possible to extend the unusually broad
utility of this Ru–NHC complex to the asymmetric hydroge-
nation of various 2-pyridones.
At the outset of our study we performed the hydrogena-
tion reaction on the readily available 6-methyl-2-pyridone
(1). This compound was treated with the preformed Ru–
NHC complex {formed in the reaction between [Ru(2-Me-
allyl)2(cod)], SINpEt·HBF4, and KOt-Bu in n-hexane} under a
pressure of 70 bar of H2 at 60 °C for 24 hours. Unfortunately,
no product was observed and only starting material was re-
covered (Table 1, entry 1).
N
H
O
N
OH
N
R
O
lactam
lactim
tautomerization
no longer
favored
Scheme 1 Tautomerization of 2-pyridone
ence of various protecting groups of the N atom (Scheme 1).
Among all the protecting groups tested, Bn, Ms, Ts, and Boc
rendered the pyridone unreactive even at harsher condi-
tions (80 bar of H2, 80 °C). However, when a sterically less
demanding methyl group was installed on the N atom of 1
(3a), hydrogenation was observed at 70 bar of H2 and 60 °C,
furnishing the corresponding product 4a with full conver-
sion and a good enantiomeric ratio of 77:23. Encouraged by
this result the two previously tested additives, Et3N and
TFA, were applied under the same conditions. While Et3N
was tolerated, it turned out that the catalytic system did
not tolerate acidic conditions. A noticeable decrease in en-
antioselectivity was observed upon lowering the pressure
to 10 bar, with the product 4a being obtained with an enan-
tiomeric ratio of 68:32 (Table 2, entry 4). Further reaction
parameter screening revealed that a combination of high
pressure and lower temperature is beneficial for the stereo-
chemical outcome. For example, at 120 bar of H2 and room
temperature the enantiomeric ratio of the product 4a could
be increased to 83:17 (Table 2, entry 8). Furthermore, in
analogy to our previous projects concerning the asymmet-
ric hydrogenation of heterocyclic compounds, the chiral li-
gand SINpEt·HBF4 was again shown to be superior to all the
other ligands tested in this study.
Next we analyzed the impact of other solvents on the
reaction outcome. When CH2Cl2 was used as the reaction
medium, only traces of racemic product were observed (8%
conversion, Table 3, entry 1). Benzene, toluene, and α,α,α-
trifluorotoluene all allowed the reaction to proceed with
very good enantioselectivity (e.r. = 83:17 to 86:14, Table 3,
entries 2–4). The perfluorinated analog of toluene, however,
completely inhibited the process (Table 3, entry 5). Surpris-
ingly, full conversion was observed when pyridine was used
as the solvent, although the enantiomeric ratio of the prod-
uct 4a was somewhat lower. This could be attributed to a
possible interaction of the nitrogen atom of pyridine with
the metal center of the active catalyst, thus compromising
the enantiorecognition of the substrate (Table 3, entry 6).
Similar reasoning could explain the lower enantiomeric ra-
tios observed with 1,4-dioxane and THF as the solvents,
while Et3N and Et2O did not interfere with the process, al-
lowing for an enantiomeric ratio of 85:15 in both cases (Ta-
ble 3, entries 7–10). Under the same conditions, the addi-
tion of H2O to THF drastically lowered the solubility of the
Table 1 Hydrogenation of the Unprotected Pyridone 1a
[Ru(2-Me-allyl)2(cod)]
SINpEt⋅HBF4, KOt-Bu
N
H
O
N
H
O
H2, n-hexane, 24 h
2
1
Entry
Additive
Pressure
(bar)
Temp
(°C)
Conversion e.r.c
(%)b
1
2
3
4
5
–
70
70
70
80
80
60
60
60
80
80
−
n/d
n/d
Et3N
TFA
–
−
−
n/d
rac
rac
>99
>99
Et3N
a General conditions: 1 (0.3 mmol), [Ru(2-Me-allyl)2(COD)] (0.015 mmol),
SINpEt·HBF4 (0.030 mmol), KOt-Bu (0.045 mmol), additive (0.3 mmol), H2,
n-hexane (1 mL), 24 h; preformed complex was used.
b Determined by GC.
c Enantiomeric ratio was determined by GC on a chiral stationary phase.
The two additives tested, Et3N and TFA, gave a negative
result as well (Table 1, entries 2 and 3). When the pressure
of H2 was increased to 80 bar and the temperature to 80 °C,
full conversion to the corresponding, although racemic,
product 6-methyl-2-piperidone (2) was observed (Table 1,
entry 4). A similar situation took place when Et3N was used
as an additive (Table 1, entry 5). The reaction presumably
proceeded through heterogeneous pathways as a precipi-
tate of ruthenium black was observed in the reaction vessel.
Hypothesizing that the potential for lactam–lactim tau-
tomerization could be responsible for the unsuccessful first
attempts with 2-pyridone 1, we next examined the influ-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1557–1562

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Table 2 Screening of the Reaction Parametersa
[Ru(2-Me-allyl)2(cod)], SINpEt⋅HBF4, KOt-Bu
H2, n-hexane, 24 h
N+
BF4
N
Me
N
O
Me
N
O
–
3a
4a
SINpEt⋅HBF4
Entry
Additive
Pressure (bar)
Temp (°C)
Conversion (%)b
e.r.c
77:23
1
2
3
4
5
6
7
8
–
70
70
60
60
60
60
30
50
40
25
>99
>99
37
Et3N
TFA
–
76:24
rac
70
10
>99
>99
>99
>99
>99
68:32
78:22
75:25
79:21
83:17
–
10
–
80
–
40
–
120
a General conditions: 3a (0.3 mmol), [Ru(2-Me-allyl)2(cod)] (0.015 mmol), SINpEt·HBF4 (0.030 mmol), KOt-Bu (0.045 mmol), additive (0.3 mmol), H2, n-hexane
(1 mL), 24 h; preformed complex was used.
b Determined by 1H NMR.
c Enantiomeric ratio was determined by GC on a chiral stationary phase.
Table 3 Solvent Screeninga
reactant 3a, delivering only trace amounts of the product
(Table 3, entry 11). The use of another protic solvent EtOH
led to the formation of the racemic product (Table 3, entry
12). Presumably using this solvent, the catalyst underwent
decomposition with release of catalytically highly active
heterogeneous ruthenium nanoparticles. The cyclic analog
of n-hexane, cyclohexane, did not change the reaction out-
come, providing the product 4a with the same enantiomer-
ic ratio of 83:17 (Table 3, entry 14). In contrast to the previ-
ously tested protic solvents, not only did the sterically hin-
dered t-AmOH (2-methyl-2-butanol) allow for full
conversion but also the enantioselectivity of the observed
product was increased to 89:11 (Table 3, entry 14). More-
over, the enantiomeric ratio could be increased further to
an impressive level of 94:6 upon lowering the reaction tem-
perature to –10 °C. It is important to note that due to the
high viscosity of t-AmOH at this temperature n-hexane was
added as an innocent co-solvent.
With the optimized conditions in hand, we moved on to
explore the scope of the reaction. A range of 2-pyridones
substituted with sterically undemanding methyl or trifluo-
romethyl groups could be successfully hydrogenated to
their corresponding products in a clean fashion with no side
products being observed (Scheme 2). By exploring different
substitution patterns for the methyl group, we found that
the 3- and 6-methyl-substituted pyridones proved the best
in terms of enantioselectivity. The model compound used in
the screening studies, 6-methyl-2-pyridone (3a), was ob-
tained with full conversion and a very high enantiomeric
ratio of 94:6, although due to high volatility, only 50% of
pure product was isolated after column chromatography.
Entry
Solvent
Conversion (%)b
e.r.c
rac
1
2
CH2Cl2
8
>99
>99
>99
–
benzene
toluene
83:17
3
86:14
86:14
n/d
4
PhCF3
5
C6F5CF3
6
pyridine
>99
>99
>99
>99
>99
6
76:24
79:21
75:25
85:15
85:15
rac
7
1,4-dioxane
THF
8
9
Et3N
10
11
12
13
14
15
16d
Et2O
H2O–THF (2:1)
EtOH
>99
>99
>99
>99
>99
rac
n-hexane
cyclohexane
t-AmOH
t-AmOH–n-hexane (1:1)
83:17
83:17
89:11
94:6
a General conditions: 3a (0.3 mmol), [Ru(2-Me-allyl)2(cod)] (0.015 mmol),
SINpEt·HBF4 (0.030 mmol), KOt-Bu (0.045 mmol), H2 (120 bar), solvent (1
mL), 25 °C, 24 h; preformed complex was used; solvent was exchanged pri-
or to the reaction.
b Determined by 1H NMR.
c Enantiomeric ratio was determined by GC on a chiral stationary phase.
d Reaction run at –10 °C.
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tiomeric ratio. The very same reaction run at sub-zero tem-
peratures led otherwise to much lower enantiomeric ratio.
In the case of 5-methyl-2-pyridone (3b) and 5-trifluoro-
methyl-2-pyridone (3e) the selectivities were much lower,
although the yields remained within a high range of 88–
90%.
[Ru(2-Me-allyl)2(cod)]
SINpEt⋅HBF4, KOt-Bu
R
R
N
O
N
O
H
2 (120 bar)
t-AmOH–n-hexane (1:1)
–10 °C, 24 h
3a–e
4a–e
At this stage we turned our attention to pyridones sub-
stituted with aromatic rings of different electronic proper-
ties (Scheme 3). We envisaged that this substantial increase
in bulkiness of the starting material may require reinvesti-
gation of the reaction parameters. While 6-phenyl-2-pyri-
done (5a) could be quantitatively converted into the corre-
sponding product at –10 °C (57:43 e.r.), all the other phe-
nyl-substituted pyridones reacted efficiently only at room
temperature. The two other analogs of 5a, that is, the pyri-
dones bearing an electron-rich (5b) and -poor (5c) phenyl
ring reacted with similarly good yields (73–75%), albeit
with low enantiomeric ratios. In comparison to 5-methyl-
2-pyridone (3b), the 5-aryl-substituted pyridones 5d–f
were converted into their corresponding products with
higher enantioselectivities, within enantiomeric ratio rang-
ing from 73:27 to 70:30. 4-Phenyl-2-pyridone (5g) was
quantitatively converted into the product 6g with a good
enantiomeric ratio of 79:21, while 3-phenyl-2-pyridone
(5h) delivered 6h, albeit without a detectable level of enan-
tioselectivity.
Me
Me
Me
N
O
N
O
N
O
4a
4b
4cc
91%, 66:34 e.r.
>99%,a 94:6 e.r.
90%,b 52:48 e.r.
Me
O
F3C
N
N
O
4d
82%,b 82:18 e.r.
4e
88%, 54:46 e.r.
Scheme 2 Scope of the hydrogenation of the methyl- and trifluoro-
methyl-substituted pyridones. a NMR conversion given. b NMR yield giv-
en. c Reaction run at 25 °C.
The 3-substituted analogue was converted into its cor-
responding product with a high yield of 82% and an enan-
tiomeric ratio of 82:18. Contrary to any other examples,
4-methyl-2-pyridone (3c) required a higher reaction tem-
perature (25 °C) in order to increase the enantioselectivity,
furnishing the product 4c in 91% of yield and 66:34 enan-
In conclusion, the first asymmetric homogeneous hy-
drogenation of 2-pyridones has been presented. The proto-
col described16 enables access to a range of different substi-
tution patterns of enantioenriched 2-piperidones. However,
[Ru(2-Me-allyl)2(cod)], SINpEt⋅HBF4
R
R
KOt-Bu, H2 (120 bar)
N
O
N
O
t-AmOH–n-hexane (1:1), 25 °C, 24 h
5a–h
6a–h
N
O
N
O
N
O
N
O
F3C
MeO
F3C
6aa,b
99%, 57:43 e.r.
6b
73%, 58:44 e.r.
6c
75%, 54:46 e.r.
6da
88%, 73:27 e.r.
MeO
N
O
N
O
N
O
N
O
6e
6f
6ga
>99%, 79:21 e.r.
6h
83%, rac
43%, 73:27 e.r.
69%, 70:30 e.r.
Scheme 3 Scope of the hydrogenation of pyridones substituted with aromatic rings. a Reaction run on a 0.5 mmol scale. b Reaction run at –10 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1557–1562

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while we are excited about this breakthrough, it is also clear
that future studies should focus on improving the level of
enantioselectivity.
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Acknowledgment
We thank Dr. Matthew N. Hopkinson for helpful discussions during
preparation of this manuscript. Generous financial support was pro-
vided by the Deutsche Forschungsgemeinschaft (Leibniz award). This
work was supported by the NRW Graduate School of Chemistry in
Münster (J.W.)
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378703.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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Sci. 2011, 2, 803. (i) Duan, Y.; Chen, M.-W.; Ye, Z.-S.; Wang, D.-S.;
Chen, Q.-A.; Zhou, Y.-G. Chem. Eur. J. 2011, 17, 7193. (j) Wang,
D.-S.; Ye, Z.-S.; Chen, Q.-A.; Zhou, Y.-G.; Yu, C.-B.; Fan, H.-J.;
Duan, Y. J. Am. Chem. Soc. 2011, 133, 8866. (k) Duan, Y.; Chen,
M.-W.; Chen, Q.-A.; Yu, C.-B.; Zhou, Y.-G. Org. Biomol. Chem.
2012, 10, 1235. (l) Duan, Y.; Li, L.; Chen, M.-W.; Yu, C.-B.; Fan,
H.-J.; Zhou, Y.-G. J. Am. Chem. Soc. 2014, 136, 7688.
(8) Wang, T.; Chen, F.; Qin, J.; He, Y.-M.; Fan, Q.-H. Angew. Chem. Int.
Ed. 2013, 52, 7172.
(9) For selected examples of hydrogenation of (benzo)thiophenes,
see: (a) Bianchini, C.; Meli, A. Acc. Chem. Res. 1998, 31, 109.
(b) Borowski, A. F.; Sabo-Etienne, S.; Donnadieu, B.; Chaudret, B.
Organometallics 2003, 22, 4803. (c) Urban, S.; Beiring, B.;
Ortega, N.; Paul, D.; Glorius, F. J. Am. Chem. Soc. 2012, 134,
15241.
(10) For selected examples of hydrogenation of (benzo)furans, see:
(a) Ohta, T.; Miyake, T.; Seido, N.; Kumobayashi, H.; Takaya, H.
J. Org. Chem. 1995, 60, 357. (b) Studer, M.; Wedemeyer-Exl, C.;
Spindler, F.; Blaser, H.-U. Monatsh. Chem. 2000, 131, 1335.
(c) Maris, M.; Huck, W.-R.; Mallat, T.; Baiker, A. J. Catal. 2003,
219, 52. (d) Kaiser, S.; Smidt, S. P.; Pfaltz, A. Angew. Chem. Int. Ed.
2006, 45, 5194. (e) Feiertag, P.; Albert, M.; Nettekoven, U.;
Spindler, F. Org. Lett. 2006, 8, 4133. (f) Ortega, N.; Urban, S.;
Beiring, B.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51, 1710.
(g) Ortega, N.; Beiring, B.; Urban, S.; Glorius, F. Tetrahedron
2012, 68, 5185. (h) Wysocki, J.; Ortega, N.; Glorius, F. Angew.
Chem. Int. Ed. 2014, 53, 8751. (i) Pauli, L.; Tannert, R.; Scheil, R.;
Pfaltz, A. Chem. Eur. J. 2015, 21, 1482.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1557–1562

1562
J. Wysocki et al.
Letter
Synlett
(11) Ortega, N.; Tang, D.-T. D.; Urban, S.; Zhao, D.; Glorius, F. Angew.
Chem. Int. Ed. 2013, 52, 9500.
(12) Zhang, J.; Chen, F.; He, Y.-M.; Fan, Q.-H. Angew. Chem. Int. Ed.
2015, 54, 4622.
(13) For the asymmetric arene hydrogenation, see: (a) Urban, S.;
Ortega, N.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 3803.
(b) Kuwano, R.; Morioka, R.; Kashiwabara, M.; Kameyama, N.
Angew. Chem. Int. Ed. 2012, 51, 4136.
(14) Selected examples of heterogeneous hydrogenation reactions of
2-pyridones: (a) Hartmann, R. W.; Reichert, M.; Göhring, S. Eur.
J. Med. Chem. 1994, 29, 807. (b) Hartmann, R. W.; Reichert, M.
Arch. Pharm. 2000, 333, 145. (c) Padwa, A.; Heidelbaugh, T. M.;
Kuethe, J. T. J. Org. Chem. 2000, 65, 2368.
mixture was suspended in 0.5 mL of hexane and stirred at 70 °C
for 16 h after which t-AmOH (0.5 mL) was added and stirred at
r.t. for 1 h. The resulted mixture was transferred under argon to
a glass vial containing a 2-pyridone (0.3 mmol) and a magnetic
stirring bar. Any applied additive (0.3 mmol) was added at this
point. The glass vial was placed in a 150 mL stainless-steel reac-
tor, and the H2 pressure was set at 120 bar. The hydrogenation
reaction was performed at the indicated temperature for 24 h.
The crude post-reaction mixture was filtered through a plug of
silica using 5% MeOH in CH2Cl2 followed by flash column chro-
matography (5% MeOH in CH2Cl2). The enantiomeric ratio of all
compounds was determined by chiral GC or HPLC.
Compound 4a: 1H NMR (300 MHz, CDCl3): δ = 3.46 (h, J = 6.4 Hz,
1 H), 2.92 (s, 3 H), 2.37 (t, J = 6.5 Hz, 2 H), 1.99–1.78 (m, 2 H),
1.76–1.54 (m, 2 H), 1.23 (d, J = 6.5 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): δ = 170.45, 54.47, 33.05, 32.21, 30.25, 19.95, 17.86. ESI-
MS: m/z calcd for [C7H13NONa]+: 150.0889; found: 150.0889.
FTIR (ATR): 1620, 1447, 1397, 1335, 1308, 1246, 1184, 1138,
(15) Zhao, D.; Beiring, B.; Glorius, F. Angew. Chem. Int. Ed. 2013, 52,
8454.
(16) General Procedure for the Asymmetric Hydrogenation
In a glovebox, [Ru(2-Me-allyl)2(cod)] (4.8 mg, 0.015 mmol),
SINpEt·HBF4 (14.5 mg, 0.031 mmol) and dry KOt-Bu (5.0 mg,
0.045 mmol) were placed in a flame-dried screw-capped
Schlenk tube equipped with a magnetic stirring bar. The
1099, 1053, 1026, 910, 853, 691, 648 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1557–1562