Asymmetric Ruthenium-Catalyzed Hydrogenation of 2,6-Disubstituted 1,5-Naphthyridines: Access to Chiral 1,5-Diaza-cis-Decalins

Article abstract of DOI:10.1002/anie.201411105

The first asymmetric hydrogenation (AH) of 2,6-disubstituted and 2,3,6-trisubstituted 1,5-naphthyridines, catalyzed by chiral cationic ruthenium diamine complexes, has been developed. A wide range of 1,5-naphthyridine derivatives were efficiently hydrogenated to give 1,2,3,4-tetrahydro-1,5-naphthyridines with up to 99% ee and full conversions. This facile and green protocol is applicable to the scaled-up synthesis of optically pure 1,5-diaza-cis-decalins, which have been used as rigid chelating diamine ligands for asymmetric synthesis.

Full text of DOI:10.1002/anie.201411105

Angewandte
Chemie
DOI: 10.1002/anie.201411105
Asymmetric Catalysis
Asymmetric Ruthenium-Catalyzed Hydrogenation of 2,6-Disubstituted
1,5-Naphthyridines: Access to Chiral 1,5-Diaza-cis-Decalins**
Jianwei Zhang, Fei Chen, Yan-Mei He, and Qing-Hua Fan*
Abstract: The first asymmetric hydrogenation (AH) of 2,6-
disubstituted and 2,3,6-trisubstituted 1,5-naphthyridines, cata-
lyzed by chiral cationic ruthenium diamine complexes, has
been developed. A wide range of 1,5-naphthyridine derivatives
were efficiently hydrogenated to give 1,2,3,4-tetrahydro-1,5-
naphthyridines with up to 99% ee and full conversions. This
facile and green protocol is applicable to the scaled-up
synthesis of optically pure 1,5-diaza-cis-decalins, which have
been used as rigid chelating diamine ligands for asymmetric
synthesis.
have been successfully hydrogenated with excellent enantio-
selectivities.[6–15] However, despite the progress made in this
field, to our knowledge, there are few successful examples
reported on the AH of polycyclic heteroarenes (containing
more than one heterocycle) because of the strong coordinat-
ing ability of the multiheteroatom-containing substrates and/
or products.[16]
Most recently, we found that the cationic ruthenium
complexes of chiral monotosylated diamines are very efficient
The 1,2,3,4-tetrahydronaphthyridine ring
system is an important structural unit in
many biologically active compounds.[1]
Their optically pure derivatives (such as
those outlined in Figure 1) have shown
great potential for pharmaceutical devel-
opment.[1b] In addition, 1,5-diaza-cis-dec-
alins, which can be obtained from the
chiral 1,2,3,4-tetrahydronaphthyridines,
are unique diamines widely used as rigid
chelating ligands in asymmetric synthe-
sis.[2,4b] Consequently, the synthesis of
these optically pure heterocycles is of
great importance. However, there are
only a few reports describing the asym-
metric synthesis of substituted 1,2,3,4-
tetrahydro-1,5-naphthyridines,[3] and the
practical synthesis of chiral 1,5-diaza-cis-
decalin derivatives is still a challenge.[4]
During the past decade, asymmetric
hydrogenation (AH) of heteroaromatic
Figure 1. Representative biologically active compounds and the retrosynthetic analysis.
compounds has proven to be a powerful method for the
synthesis of optically active compounds with chiral hetero-
cyclic skeletons.[5] A number of heteroaromatic substrates
catalysts for AH of quinolines[6c,d] and quinoxalines[8b] with
excellent reactivity and enantioselectivity. Particularly, this
catalytic system has been demonstrated to be highly enantio-
selective for the AH of challenging polycyclic 1,10-phenan-
throlines.[16a] Encouraged by these results and given our
continuing interest in the application of this phosphine-free
catalytic system[17] to the hydrogenation of more challenging
substrates, we envisioned that it could be applied to the yet
unsolved AH of 2,6-disubstituted 1,5-naphthyridine deriva-
tives[18,19] to give the corresponding 1,2,3,4-tetrahydronaph-
thyridines, and consequently provide easy access to chiral 1,5-
diaza-cis-decalins (e.g., D; Figure 1). Herein, we report the
first highly efficient AH of 2,6-disubstituted 1,5-naphthyri-
dine derivatives with excellent enantioselectivity.
[*] J. Zhang, F. Chen, Y.-M. He, Prof. Dr. Q.-H. Fan
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences (ICCAS)
Beijing 100190 (P. R. China)
and
Collaborative Innovation Center of Chemical Science and Engi-
neering, Tianjin 300072 (P. R. China)
E-mail: fanqh@iccas.ac.cn
[**] We thank the National Basic Research Program of China (973
Program, No. 2011CB808600), the National Natural Science
Foundation of China (Nos. 21232008 and 21473216), and ICCAS for
financial support.
In our initial study, the AH of 2,6-dimethyl-1,5-naphthyr-
idine (1a) with the catalyst (R,R)-3a (see Table 1) was chosen
as the model reaction for the optimization of the reaction
conditions. As seen from Table S1 (see the Supporting
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411105.
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Table 1: AH of 2,6-disubstituted and 2,3,6-trisubstituted 1,5-naphthyr-
Information), ethanol was found to be optimal in terms of
both reactivity and enantioselectivity. Upon the screening of
a variety of catalysts, the catalyst bearing the hexamethyl-
benzene ligand (R,R)-3b was found to give the highest
enantioselectivity (99% ee; see Table S2 in the Supporting
Information). In addition, the enantioselectivity of the
reaction was insensitive to hydrogen pressure and temper-
ature (see Table S3 in the Supporting Information). Notably,
when the catalyst loading of (R,R)-3b was decreased to
0.2 mol%, identical enantioselectivity was still observed.
Under the optimized reaction conditions, a variety of 2,6-
dialkyl-substituted 1,5-naphthyridines (1a–f) were smoothly
hydrogenated in the presence of 0.2 mol% (R,R)-3b, thus
affording the corresponding chiral tetrahydronaphthyridines
with excellent enantioselectivities (89–99% ee; Table 1).
Substrates bearing long or branched alkyl substituents like
isobutyl and n-hexyl gave slightly lower enantioselectivities
(1d and 1e). The unsymmetrical 2,6-dialkyl-substituted 1,5-
naphthyridine substrate 1 f was hydrogenated with high
enantioselectivity, albeit with low regioselectivity. Moreover,
substrates bearing one phenyl substituent at the 2-position
(1g–j) could also be reduced with excellent enantioselectiv-
ities (98–99% ee). 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 at the 2-position had no apparent effect on
enantioselectivity (1g–j).
idines.[a]
The hydrogenation of 2,6-diaryl-substituted 1,5-naphthyr-
idines were also examined. To our delight, hydrogenation of
1k, performed in a mixture of isopropanol (IPA) and toluene,
with 2.0 mol% (R,R)-3a as the optimal catalyst, gave good
enantioselectivity (see Table S4 in the Supporting Informa-
tion). Under the optimized reaction conditions, all 2,6-diaryl-
substituted 1,5-naphthyridines (1k–o; Table 1) were hydro-
genated with full conversions and very good enantioselectiv-
ities (80–85% ee). After a single recrystallization from
petroleum ether and CH2Cl2, 2l with 98% ee could be
obtained. It was found that the electronic properties of the
substituents at the phenyl ring could influence the regiose-
lectivity of the reaction. For the unsymmetrical 2,6-diaryl-
substituted substrates (1m–o), the pyridyl rings bearing more
electron-rich substituents are more easily reduced.
Encouraged by the above exciting results, AH of the more
challenging 2,3,6-trisubstituted 1,5-naphthyridines (1p–r;
Table 1) were further investigated with the catalyst (R,R)-3c
(1.0 mol%). Notably, all the three substrates were hydro-
genated smoothly to give reduced products in full conversions
but with quite different regioselectivity. For the cyclic
substrates 1p and 1q, excellent diastereoselectivities were
obtained, and the enantioselectivities increased from 12 to
85% ee when the cycle becomes larger. Unexpectedly, for the
acyclic substrate 2r, a clear selectivity for the hydrogenation
of the pyridyl ring bearing a phenyl group was observed, and
moderate enantioselectivity was obtained.
[a] Reaction conditions: substrate (0.6 mmol) in 1.0 mL of EtOH, (R,R)-
3b (0.2 mol%), 50 atm of H2, stirred at 208C for 10 h. Yields of isolated
products are given (for 1n and 1o, yields are determined by 1H NMR
spectroscopy). Enantiomeric excesses were determined by HPLC
analysis using a chiral column. [b] Used 1k–o (0.2 mmol) in 1.0 mL of
IPA/toluene (1/1, v/v), and (R,R)-3a (2.0 mol%). [c] The absolute
configurations were assigned by analogy to 2a and 2l, respectively (see
Schemes S1 and S2),[20] which were characterized by single-crystal X-ray
analysis. [d] After recrystallization from petroleum ether/CH2Cl2 (1:1,
v/v). [e] Data in brackets are yields of the other regioselective product in
which the pyridyl rings bearing electron-withdrawing substituents were
hydrogenated. [f] Used 1p–r (0.2 mmol) in 1.0 mL of methanol, (R,R)-3c
(1.0 mol%).
assigned as R by single-crystal X-ray analysis.[20] The config-
urations of the other chiral products are assigned by analogy.
Based on these results and to further understand the
origin of stereoselectivity, we propose the cyclic 10-membered
transition states for the AH of 2,6-disubstituted 1,5-naph-
thyridines (Figure 2). In the case of substrates bearing at least
one alkyl group at the 2-position, the transition state is similar
to the one we proposed previously for the AH of quinoline.[6d]
Notably, for 2,6-diaryl-substituted 1,5-naphthyridines, the
The absolute configuration of 2a was determined to be R
based on single-crystal X-ray analysis of N-tosyl-2,6-
dimethyl-tetrahydro-naphthyridine (2s; see Scheme S1 in
the Supporting Information).[20] Similarly, the configuration
of 2l (see Scheme S2 in the Supporting Information) was
2
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In conclusion, we have developed the first highly enan-
tioselective hydrogenation of 2,6-disubstituted and 2,3,6-
trisubstituted 1,5-naphthyridines using chiral cationic ruthe-
nium diamine catalysts with good to excellent enantioselec-
tivities. Moreover, this new method provides a practical and
facile approach to the synthesis of optically pure 1,2,3,4-
tetrahydronaphthyridines and 1,5-diaza-cis-decalin deriva-
tives. Further studies on a detailed mechanism and applica-
tion of the unique chiral cyclic diamines in asymmetric
synthesis are in progress.
Received: November 16, 2014
Revised: December 29, 2014
Published online: && &&, &&&&
Figure 2. Proposed transition states involving (R,R)-3a and (R,R)-3b
as the catalysts.
enantioselectivity originates from the CH–p attraction
between the h6-arene ligand in the ruthenium complex and
the substituted phenyl ring, instead of the fused pyridine ring.
The hydride is transferred from the ruthenium center to the Si
Keywords: asymmetric catalysis · enantioselectivity ·
heterocycles · hydrogenation · ruthenium
.
=
face of the C N moiety to give the R-configured product. This
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Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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Asymmetric Catalysis
J. Zhang, F. Chen, Y.-M. He,
Q.-H. Fan*
&&&& — &&&&
Asymmetric Ruthenium-Catalyzed
Hydrogenation of 2,6-Disubstituted 1,5-
Naphthyridines: Access to Chiral 1,5-
Diaza-cis-Decalins
Enantioselective hydrogenation of 2,6-
disubstituted 1,5-naphthyridines pro-
ceeds in the presence of the cationic
ruthenium diamine complexes with
excellent enantioselectivities. This
method provides an easy and practical
access to optically pure 1,5-diaza-cis-dec-
alins.
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