Ruthenium-Catalyzed Enantioselective Hydrogenation of 1,8-Naphthyridine Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b01186

The first asymmetric hydrogenation of 2,7-disubstituted 1,8-naphthyridines catalyzed by chiral cationic ruthenium diamine complexes has been developed. A wide range of 1,8-naphthyridine derivatives were effectively hydrogenated to give 1,2,3,4-tetrahydro-1,8-naphthyridines with up to 99% ee and full conversions. The method provides a practical and facile approach to the preparation of valuable chiral heterocyclic building blocks and useful motifs for a new kind of P,N-ligand.

Full text of DOI:10.1021/acs.orglett.6b01186

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Enantioselective Hydrogenation of 1,8-
Naphthyridine Derivatives
Wenpeng Ma,† Fei Chen,† Youran Liu,† Yan-Mei He,† and Qing-Hua Fan*,†,‡
†CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences (ICCAS),
Beijing 100190, P. R. China
‡Collaborative Innovation Center of Chemical Science and Engineering, Tianjing 300072, P. R. China
S
* Supporting Information
ABSTRACT: The first asymmetric hydrogenation of 2,7-
disubstituted 1,8-naphthyridines catalyzed by chiral cationic
ruthenium diamine complexes has been developed. A wide
range of 1,8-naphthyridine derivatives were effectively hydro-
genated to give 1,2,3,4-tetrahydro-1,8-naphthyridines with up
to 99% ee and full conversions. The method provides a
practical and facile approach to the preparation of valuable
chiral heterocyclic building blocks and useful motifs for a new kind of P,N-ligand.
he 1,2,3,4-tetrahydro-1,8-naphthyridine ring systems are
attractive structural motifs because of their wide
distribution in bioactive molecules and pharmaceuticals, as
represented by a potent antagonist of the αvβ3 receptor,1 CETP
(cholesterol ester transfer protein) inhibitor,2 and EP1
(prostaglandin E1 receptor 1) antagonist3 (Figure 1). To
enantioselectivity (Scheme 1).8c Encouraged by these results,
we hope to expand the substrate scope from 1,5-naphthyridines
T
Scheme 1. Asymmetric Hydrogenation of Naphthyridine
Derivatives
Figure 1. Representative biologically active compounds.
to 1,8-naphthyridines, which are usually regarded as difficult
substrates due to their strong coordinating abilities. To date,
only a few examples were reported, and most of them included
heterogeneous regioselective hydrogenation.1a,b,3,4e,f Most
recently, Zhang and co-workers reported a novel straightfor-
ward synthesis of 1,2,3,4-tetrahydronaphthyridines via a
ruthenium-catalyzed selective transfer hydrogenation of a
pyridyl ring with alcohols.4g However, only racemic products
were obtained. Herein, we report the first highly efficient
asymmetric hydrogenation of a range of 1,8-naphthyridine
derivatives with good to excellent enantioselectivities and full
conversions.
date, many methods have been developed for the preparation of
1,2,3,4-tetrahydro-1,8-naphthyridines such as hydroboration of
naphthyridine,4a intramolecular Chichibabin cyclization,1c,d,4b
tin-free radical cyclization,4c ortho-alkylation of Boc-protected
aminopyridines,4d regioselective hydrogenation,1a,b,3,4e,f and
transfer hydrogenation of naphthyridines.4g However, the
asymmetric synthesis of 1,2,3,4-tetrahydro-1,8-naphthyridine
derivatives is rare.1c,d
In the past decade, asymmetric hydrogenation of hetero-
aromatic compounds has become one of the most straightfor-
ward ways toward the synthesis of optically active compounds
with chiral heterocyclic skeleton.5−8 In this context, we found
that the phosphine-free, cationic ruthenium complexes of chiral
monotosylated diamine are highly effective catalysts for
asymmetric hydrogenation of quinolines,6b,c quinoxalines,7e
and 1,10-phenanthrolines8a with unprecedentedly high reac-
tivities and excellent enantioselectivities. Very recently, we
applied the cationic ruthenium complexes to the hydrogenation
of 1,5-naphthyridine derivatives with excellent regio- and
In the initial experiment, 1,8-naphthyridine was chosen to be
hydrogenated with (R,R)-3a in iPrOH under 50 atm of H2.
However, 1,2,3,4-tetrahydro-1,8-naphthyridine was not de-
tected (Table 1, entry 1). In contrast, 1,5-naphthyridine
Received: April 23, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b01186
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Letter
Table 1. Comparison of Hydrogenation Activity between
1,8-Naphthyridines and 1,5-Naphthyridines
Scheme 2. Asymmetric Hydrogenation of 2,7-Disubstituted
and 2,3,7-Trisubstituted 1,8-Naphthyridines
a
a
a
Reaction conditions: substrate (0.1 mmol), iPrOH (1 mL), (R,R)-3a,
b
H2 (50 atm), stirred at 25 °C. S/C = substrate/catalyst. Determined
c
by 1H NMR. The ee values were determined by a chiral OD-H
d
column. About 7% byproduct was observed, and substrate can be
recovered. Data were reported in ref 8c.
e
could be hydrogenated smoothly in 92% yield under the same
conditions (entry 2). The result indicated that the ruthenium
catalyst was deactivated by the 1,8-naphthyridine substrate. We
envisioned that the introduction of a substituent at the ortho
position of both pyridyl rings could reduce their coordinating
ability.9 To our delight, 2,7-dimethyl-1,8-naphthyridine could
be hydrogenated by using 1.0 mol % catalyst, giving the desired
chiral product in 64% yield with 94% ee. Slightly higher
enantioselectivity was achieved although a much lower yield
was observed as compared with 2,6-dimethyl-1,5-naphthyridine
(entry 3 vs 4). These results illustrated that 1,8-naphthyridines
were much more difficult substrates for hydrogenation than 1,5-
naphthyridines.
Encouraged by these promising results, the influences of
solvent, catalyst, temperature, and hydrogen pressure were
studied by using 2,7-dimethyl-1,8-naphthyridine 1a as the
model substrate and (R,R)-3a as the catalyst (see the
Supporting Information (SI)). After a number of solvents
were screened, isopropanol was found to be optimal in terms of
reactivity and enantioselectivity (Table S1, SI). Then, the
influence of different catalysts was investigated by using
isopropanol as the solvent (Table S2, SI). Further improvement
of enantioselectivity was achieved by using the ruthenium
catalyst bearing a hexamethylbenzene ligand (R,R)-3f (99% ee).
In addition, the enantioselectivity of the reaction was found to
be insensitive to hydrogen pressure and temperature (Table S3,
SI).
a
Reaction conditions: substrates 1a−l (0.2 mmol), iPrOH (1 mL), 2.0
mol % of (R,R)-3f, H2 (50 atm), stirred at 25 °C for 12 h; substrates
1m−u (0.2 mmol), nBuOH (1 mL), 5.0 mol % of (R,R)-3a, 50 atm of
H2, stirred at 25 °C for 24 h. Yields of isolated product were given.
The ee values were determined by chiral HPLC analysis. The absolute
configuration of 2i was determined to be R and 2m was determined to
be S based on single-crystal X-ray analysis (Schemes S1, S3, SI). The
configurations of the other products were proposed by analogy.
one aryl substituent at the 7-position (1f−l), excellent
enantioselectivities were also obtained. Interestingly, only the
pyridyl ring bearing an alkyl group was hydrogenated. Notably,
the electronic properties of the substituents at the para position
of the phenyl ring had no apparent effect on enantioselectivity
(1f−j). Substrate 1l bearing a 2-thienyl substituent gave
obviously low enantioselectivity.
The hydrogenation of 2,7-diaryl-substituted 1,8-naphthyr-
idines were also examined. From the screening of a variety of
solvents (Table S4, SI) and catalysts (Table S5, SI) using 1m as
the model substrate, the optimal reaction conditions were
determined to be 5.0 mol % (R,R)-3a in nBuOH. Subsequently,
a variety of 2,7-diaryl-substituted 1,8-naphthyridines (1m−t)
were evaluated. As shown in Scheme 2, all 2,7-diarylsubstituted
substrates were hydrogenated with full conversions and
moderate to good enantioselectivities. Notably, substrates
bearing strong electron-donation group 1o and strong
electron-withdrawing group 1p at the para positions of both
phenyl rings gave much lower enantioselectivities. In the cases
of unsymmetrical 2,7-diarylsubstituted substrates (1q−r), the
With the optimized reaction conditions in hand, we turned
our attention to investigate the scope of the disubstituted 1,8-
naphthyridine derivatives, and the results were summarized in
Scheme 2. Generally, 2,7-dialkyl-substituted 1,8-naphthyridines
were hydrogenated smoothly in the presence of 2.0 mol %
(R,R)-3f with excellent enantioselectivities (97−99% ee)
regardless of the length of the side chain (1a−c, 1e in Scheme
2). Substrate bearing steric alkyl substituent 1d gave obviously
low enantioselectivity. Moreover, for the unsymmetrical
substrates bearing one alkyl substituent at the 2-position and
B
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pyridyl ring bearing an electron-rich substituent was preferred
to be hydrogenated. Interestingly, substrate 1s bearing a
methoxy group at the ortho position of one phenyl ring gave
excellent regioselectivity and high enantioselectivity (91% ee).
2,7-Dithienyl-substituted substrate 1t was hydrogenated with
84% ee. In addition, 2,3,7-trisubstituted 1,8-naphthyridine 1u
could be hydrogenated smoothly with moderate enantioselec-
tivity but much lower regioselectivity.
The absolute configuration of 2i was determined to be R
based on single-crystal X-ray analysis (Scheme S1, SI).
Similarly, the configuration of 2m was assigned as S by
single-crystal X-ray analysis of the corresponding N-tosylated
derivative compound 5 (Scheme S3, SI). The configurations of
the other chiral products were assigned by analogy.
Based on these results and our previous study on the
asymmetric hydrogenation of quinoline,6c we proposed a cyclic
10-membered transition structure with the participation of the
TfO anion for the asymmetric hydrogenation of 1,8-
naphthyridines. For both types of substrates bearing an alkyl
or aryl group at the 2-position, the enantioselectivity originates
from the CH−π interaction between the η6-arene ligand in the
ruthenium complex and the fused pyridine ring (TS1 and TS2
in Figure 2). Notably, in the case of 2,7-diaryl-substituted 1,8-
provides an easy way for the construction of optically pure
1,2,3,4-tetrahydro-1,8-naphthyridine ring systems which are key
substructures in bioactive molecules and pharmaceuticals. In
addition, these chiral compounds are of great interest in the
development of a new kind of modular P−N ligand. Further
studies on the synthesis and application of these new P−N
ligands are in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01186.
X-ray data for compound 2i (CIF)
X-ray data for compound 5 (CIF)
Experimental procedures, the synthesis method of the
starting materials, and compound characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: fanqh@iccas.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21232008, 21402041, and 21521002) and ICCAS for
financial support.
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