Ruthenium-Catalyzed Straightforward Synthesis of 1,2,3,4-Tetrahydronaphthyridines via Selective Transfer Hydrogenation of Pyridyl Ring with Alcohols

Article abstract of DOI:10.1021/acs.orglett.5b01976

Through a ruthenium-catalyzed selective hydrogen transfer coupling reaction, a novel straightforward synthesis of 1,2,3,4-tetrahydronaphthyridines from o-aminopyridyl methanols and alcohols has been developed. The synthetic protocol proceeds in an atom- a

Full text of DOI:10.1021/acs.orglett.5b01976

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Straightforward Synthesis of 1,2,3,4-
Tetrahydronaphthyridines via Selective Transfer Hydrogenation of
Pyridyl Ring with Alcohols
Biao Xiong, Ya Li, Wan Lv, Zhenda Tan, Huanfeng Jiang, and Min Zhang*
School of Chemistry & Chemical Engineering, South China University of Technology, Wushan Rd-381, Guangzhou 510641, People’s
Republic of China
S
* Supporting Information
ABSTRACT: Through a ruthenium-catalyzed selective hydro-
gen transfer coupling reaction, a novel straightforward
synthesis of 1,2,3,4-tetrahydronaphthyridines from o-amino-
pyridyl methanols and alcohols has been developed. The
synthetic protocol proceeds in an atom- and step-economic
fashion together with the advantages of operational simplicity, broad substrate scope, production of water as the only byproduct,
and no need for external reducing reagents such as high pressure H2 gas, offering a highly practical approach for accessing this
type of structurally unique products.
Scheme 1. Conventional Methods and This Work
he selective hydrogenation of aromatic hydrocarbons is an
attractive but challenging task in organic chemistry. Its
T
significance lies in the applications in both organic synthesis and
hydrogen energy storage. Pioneered by Birch1 and Benkeser2
reduction, the conventional hydrogenation with high-pressure
H2 gas3,4 and the transfer hydrogenation with specific reducing
agents5 are the common approaches. In comparison, the transfer-
hydrogenation reactions at atmospheric pressure do not neefor
special equipment such as autoclaves, offering more convenient
and safer operations. However, such processes typically produce
stoichiometric amounts of waste. To utilize the feedstock atoms
to a maximum extent, the hydrogen-borrowing strategy using
abundant and sustainable alcohols as both hydrogen sources and
coupling partners represent an interesting tool in synthetic
chemistry,6 in which the in situ formed C−C or C−N double
bond serve as the hydrogen abstractors. Despite these advances,
the development of hydrogen-transfer coupling reactions7 with
alcohols by exploring aromatic systems as both hydrogen
absorbers and coupling components remains a new challenging,
but highly desirable subject, which would not only enrich the
hydrogenation of aromatic system but also pave new pathways to
access functional products.
1,2,3,4-Tetrahydronaphthyridines (THNADs) constitute an
important class of structurally unique compounds, exhibiting
diversely interesting biological and therapeutic activities.8−13
Moreover, THNADs serve as versatile building blocks for various
synthetic purposes including the preparation of functionalized
materials.14 Generally, THNADs were prepared starting from 2-
aminopyridine derivatives via step-by-step operations including
nucleophilic addition to acrylic acid, intramolecular dehydrative
cyclization, and reduction with boron hydrides (Scheme 1,
method 1)14b,d or amino protection, benzylic bromination,
deprotection/intermolecular cyclization with ketones, and
reduction (method 2).10,15 Despite these valuable contributions,
the multistep synthesis using either waste-producing or less
environmentally benign halogenated reagents could constantly
limit their synthetic utility and cause environmental issues.
Alternatively, an initial step leading to naphthyridines, followed
by hydrogenation with H2 gas, has offered interesting new access
to the related end (method 3).10,12 Nevertheless, the develop-
ment of versatile shortcuts to access THNADs from easily
available feedstocks still remains a highly demanding goal.
Through a ruthenium-catalyzed selective hydrogen transfer
coupling reaction, we herein report a novel straightforward
synthesis of THNADs 3 from o-aminopyridyl methanols 1 and
Received: July 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01976
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Letter
alcohols 2. In the redox pair, the pyridyl ring and two alcohol
units serve as the hydrogen acceptor (oxidant) and hydrogen
donors (reductants), respectively. Hence, there is no need for
using any external reductants, offering a facile synthesis of
THNADs in an atom- and step-economic fashion (method 4).
We initiated our investigation to determine an efficient
reaction system.16 The synthesis of 7-p-tolyl-1,2,3,4-tetrahydro-
1,8-naphthyridine 3aa from (2-aminopyridin-3-yl)methanol 1a
and 1-p-tolylethanol 2a was chosen as a model reaction to
evaluate the effect of representative precatalysts, ligands, different
reaction time, temperatures, and solvents. An optimal yield and
selectivity of 3aa were obtained at 130 °C by using Ru3(CO)12/
xanthphos/t-BuOK as a catalyst system and tert-amyl alcohol as
solvent (see the Supporting Information, Table S1).
With the optimized reaction conditions established, we then
examined the generality and the limitations of this ruthenium-
catalyzed protocol. First, the reactions of 1a in combination with
a wide range of alcohols (see the Supporting Information
Scheme S2, for the structures of substrates) were examined. As
shown in Scheme 2, all of the reactions proceeded efficiently and
The reactions of cyclic alcohols (2e,f) gave the corresponding tri-
and tetracyclic products in good yields in 10 h (3ae−af). These
examples demonstrate the potential of the synthetic protocol for
the construction of various annulated heterocycles. Further
investigations showed that alkyl alcohols (2g−j) were also
effective coupling partners to afford the non-, mono-, and
dialkylated products in moderate to high yields (3ag−aj). 2-
Phenylethan-1-ol 2k demonstrated remarkable reactivity to
couple with 1a at 115 °C, resulting in a 6-phenyl product 3ak
in 5 h with excellent yield, and its structure was confirmed by X-
ray diffraction (see the Supporting Information, Figure 1).
Further, both alkyl and aryl groups could be flexibly introduced
into the newly formed pyridyl skeleton by tuning the alcohols
(3al,am). Notably, 1-phenylpropan-2-ol 2m led to three
regioisomers, and the C−C coupling mainly took place at the
more active benzylic position (see 3am,am1). Interestingly, the
pyridyl unit containing alcohols 2n and 2o also underwent
efficient hydrogen-transfer coupling reactions to afford bipyridyl
products (3an,ao), which are important ligands that could be
applied in transition-metal catalysis and the preparation of
functional organometallic materials.18
In addition to the alcohols 2, we subsequently turned our
attention to the utilization of o-aminopyridyl methanols 1 with
different substitution patterns (Scheme 3). Similar to the results
Scheme 2. Synthesis of THNADs from 1a and Alcohols
Scheme 3. Synthesis of THNADs from Various o-
Aminopyridyl Methanols and Alcohols
Reaction conditions: Unless otherwise stated, all reactions were carried
out under nitrogen atmosphere by using 1a (0.5 mmol), 2 (0.5 mmol),
catalyst (1 mol %), ligand (3 mol %), t-BuOK (50 mol %), tert-amyl
a
b
alcohol (1.2 mL), temperature (130 °C). Isolated yield. GC ratio of
c
d
e
3 and 3′. Reaction time. 2g (1.5 mmol). Reaction temperature: 115
°C.
Reaction conditions: Unless otherwise stated, all reactions were carried
out under nitrogen atmosphere by using 1 (0.5 mmol), 2 (0.5 mmol),
catalyst (1 mol %), ligand (3 mol %), t-BuOK (50 mol %), t-amyl
the transfer hydrogenation mainly occurred at the sterically less-
hindered pyridyl ring, affording the desired products exclusively
(3ae−ag,aj,al,ao) or with excellent regioselectivity (3aa−ad,ah−
ai,ak). Except for the steric influence, the conjugated effect might
be another crucial factor in controlling the hydrogenation
selectivity, because a stable conjugated system disfavors the
pyridyl reduction in the case of pyridyl skeleton bearing a aryl
substituent (see 3aa−ad,af,ak−ao). Specifically, 1-aryl ethanols
(2a−d) afforded the 7-aryl THNADs in good to excellent yields
in 8 h (3aa−ad). Owing to possessing a 2-arylpyridine structural
unit, these products have the potential for further elaboration of
complex molecules via direct C−H bond functionalization.17
a
b
alcohol (1.2 mL), temperature (130 °C). Isolated yield. GC ratio of
c
d
e
3 and 3′. Reaction time. t-BuOK: 0.5 mmol. 2g, 2h: 1.5 mmol.
described in Scheme 2, all of the reactions proceeded with high or
exclusive transfer hydrogenation selectivity, affording the desired
products in moderate to good yields upon isolation. As compared
to substrate 1a, (2-amino-6-methylpyridin-3-yl)methanol 1b
reacting with several representative alcohols afforded the
corresponding products in relatively lower yields (3ba−bc,bk),
presumably due to the influence of steric effect. Gratifyingly, (3-
aminopyridin-2-yl)methanol 1c also could be transformed into
B
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the 1,2,3,4-tetrahydro-1,5-naphthyridines in reasonable yields
(3ck,cb). However, the reaction of (4-aminopyridin-3-yl)-
methanol 1d with 2b only yielded a trace of product 3db,
indicating the nitrogen atom in the pyridyl ring of substrate 1
ortho to the amino or the hydroxymethyl group is essential to
obtaining a satisfactory yield. As expected, (3-aminopyrazin-2-
yl)methanol 1e could react with 1b to afford product 3eb in 63%
yield. Noteworthy, the transfer hydrogenation occurred
exclusively on the newly formed pyridiyl ring while using more
bulky substrate 1f with less substituted ethanol 2g or 2-propanol
2h (3fg′,fh′).
deuteration at position 5 of product 3ah supports that a
reversible hydrogenation process takes place in this step (see the
Supporting Information, Scheme S3). Then, the consumption of
1′ and 2′ via cross double condensations would switch the
equilibrium toward the dehydrogenation direction, affording 1,8-
naphthyridine 3s′ along with liberation of water. Finally, the
ruthenium-catalyzed transfer hydrogenation of the pyridyl ring
gives product 3 or 3′. Through theoretical calculation for
contrastive energy of the regio-isomers, it clearly reveals that the
product selectivity correlates with their thermodynamic stability
(see the Supporting Information, Tables S10 and S11).
Finally, we were interested in exploring the utility of the
synthetic method. We applied it to the rapid synthesis of product
5a, a therapeutic composition used for the treatment of TNF-α-,
IL-1β-, IL-6-, and/or IL-8-mediated diseases such as inflamma-
tion, pain, and diabetes (Scheme 6).6 Initially, the synthesis of
To gain insight into the possible mechanism, the model
reaction was interrupted after 1 h to analyze the reaction
intermediates. By means of GC analyses, both products 3aa and
3sa′ were observed in 29% and 28% yields, respectively (Scheme
4, eq 1), indicating the forming rate of 3sa′ is much faster than
Scheme 4. Control Experiments
Scheme 6. Utility of the Synthetic Method
3ab was scaled up by using 10 mmol of substrates, which still
afforded a good product yield upon isolation (step 1:81%, 1.7 g).
Then, the palladium-catalyzed C−N coupling product 4a from
3ab and 4-chloro-2-(methylthio)pyrimidine was obtained in
71% yield under the optimized reaction conditions (see the
Supporting Information, Table S2). Ultimately, the substitution
of the methylthio group in 4a using excess 2-phenylethanamine
afforded the desired product in 92% yield (see the Supporting
Information for the synthesis of 5a).
In summary, we have developed a novel straightforward
synthesis of 1,2,3,4-tetrahydronaphthyridines (THNADs). By
employing a commercially available catalyst system, a series of o-
aminopyridyl methanols were efficiently converted in combina-
tion with different types of alcohols into various desired products
in moderate to excellent isolated yields. Moreover, the utility of
the method is demonstrated through a rapid synthesis of a
therapeutic product. The synthetic protocol proceeds in an
atom- and step-economic fashion together with the advantages of
operational simplicity, broad substrate scope, water as the only
byproduct, and no need for external reducing reagents, offering a
tunable and practicable approach for the construction of this type
of structurally unique product. Further investigation utilizing the
hydrogen-transfer coupling strategy in other heterocyclic
systems as well as the asymmetric synthesis is ongoing in our
laboratory and will be reported in due course.
that of the reduction process. Hence, the transfer hydrogenation
step is believed to be a rate-determining step in the whole
reaction. Furthermore, 3sa′ was separated to react with 2 equiv of
2a, and product 3aa was detected in almost quantitative GC yield
along with small portion of 3aa′ (eq 2), showing 3sa′ is a key
reaction intermediate and the annulation step should occur prior
to the reduction of the pyridyl unit. However, that 3sa′ failed to
yield even a trace of 3aa in the absence of 2a indicates the alcohol
serves as a hydrogen supplier during the transfer hydrogenation
process (not listed). Moreover, both reactions of 2-amino-
nicotinaldehyde 1a′ with 2 equiv of 2a or 2 equiv of 1a with
ketone 2a′ gave product 3aa in excellent yields (eqs 3 and 4),
implying that 1a′ and 2a′ are the reaction intermediates.
On the basis of the above-observed findings, a plausible
reaction pathway is proposed in Scheme 5. The reaction initiates
via ruthenium-catalyzed dehydrogenation of alcohol units of 1
and 2 to form the corresponding carbonyl intermediates 1′ and
2′. Through a deuterium-labeling experiment, the partial
Scheme 5. Possible Pathway for the Formation of 3
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01976.
Experimental procedures and spectral data (PDF)
C
DOI: 10.1021/acs.orglett.5b01976
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Letter
H.; Leu, C.-T.; Rodan, S. B.; Rodan, G. A.; Duong, L. T.; Hartman, G. D.
Bioorg. Med. Chem. Lett. 2004, 14, 1049.
(9) Selected examples on potent antagonist of vitronectin and integrin:
(a) Manley, P. J.; Miller, W. H.; Uzinskas, I. N. PCT Int. 017959, 2001.
(b) Miller, W. H.; Manley, P. J. PCT Int. 033838, 2000.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: minzhang@scut.edu.cn.
Notes
(10) Selected example on potent antagonist of integrin receptor:
Nagarajan, S. R.; Khanna, I. K.; Clare, M.; Gasiecki, A.; Rogers, T.; Chen,
B.; Russell, M.; Lu, H.-F.; Yi, Y.; Huff, R. M. U.S. Patent 0092538, 2004.
(11) Selected examples on inhibitors of bacterial enoyl-ACP reductase:
Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess, W. J.; DeWolf,
W. E., Jr; Elkins, P. A.; Head, M. S.; Jakas, D. R.; Janson, C. A.; Keller, P.
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F.-P.; Meyer, R.; Nau, W. M.; Atkinson, J.; Rintoul, J.; Pratt, D. A.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21472052), Science Foundation for Distinguished Young
Scholars of Guangdong Province (2014A030306018), and the
Fundamental Research Funds for the Central Universities
(2014ZZ0047, 2015PT018) for financial support.
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