Silver-Catalyzed Reduction of Quinolines in Water

Article abstract of DOI:10.1021/acs.orglett.9b01055

A ligand- and base-free silver-catalyzed reduction of quinolines and electron-deficient aromatic N-heteroarenes in water has been described. Mechanistic studies revealed that the effective reducing species was Ag-H. This versatile catalytic protocol provided facile, environmentally friendly, and practical access to a variety of 1,2,3,4-tetrahydroquinoline derivatives at room temperature.

Full text of DOI:10.1021/acs.orglett.9b01055

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver-Catalyzed Reduction of Quinolines in Water
Yan Wang,† Baobiao Dong,‡ Zikun Wang,*,‡ Xuefeng Cong,‡ and Xihe Bi*,‡
†School of Chemistry and Life Science, Changchun University of Technology, Changchun 130012, China
‡Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
S
* Supporting Information
ABSTRACT: A ligand- and base-free silver-catalyzed reduction of
quinolines and electron-deficient aromatic N-heteroarenes in water has
been described. Mechanistic studies revealed that the effective reducing
species was Ag−H. This versatile catalytic protocol provided facile,
environmentally friendly, and practical access to a variety of 1,2,3,4-
tetrahydroquinoline derivatives at room temperature.
ransition metal−hydride complexes have attracted a great
deal of attention in recent years, due to their efficient and
inspired us to explore the reduction of N-heteroarenes by using
Ag−H as the reducing species in water.
T
unique performance observed in hydrogenation of organic
compounds.1 A vast number of transition metal−hydride
complexes, such as rhodium,2 ruthenium,3 palladium,4
iridium,5 iron,6 and cobalt,7 have shown excellent activity in
homogeneous hydrogenation. However, the hydrogenations
with silver−hydride (Ag−H) complexes have rarely been
explored. Only a few examples have concerned the utilization
of Ag−H sources in the reduction of aldehydes (Figure 1a).8
We initiated our investigation with the reduction of 2-
methylquinoline (1a) using PhSiH3 as the reducing reagent
with a silver catalyst. Only a trace amount of hydrogenated
product 2-methyl-1,2,3,4-tetrahydroquinoline (2a) was ob-
served in the presence of 10 mol % AgOTf in toluene at room
temperature (Table 1, entry 1). Other solvents, such as hexane,
dichloroethane (DCE), and CHCl3, were also found to be
ineffective (entries 2−4, respectively). When the reaction was
carried out in ethanol or water at room temperature for 10
min, excellent yields were obtained (entry 5 or 6, respectively).
Decreasing the load of AgOTf to 5 mol % resulted in a 97%
isolated yield of the desired product (entry 7). Importantly, no
product was detected in the absence of the silver catalyst
(entry 8). Among the SiH sources examined, PhSiH3 and
Ph2SiH2 gave a similar result, but the reaction was completely
shut down while using PMHS, DEMS, and Ph3SiH (entries 9−
12). In addition, AgOAc and Ag3PO4 also provided the
reduction product in good yields (entries 13 and 14,
respectively).
With the optimized reaction conditions established, we first
studied the scope of C2-substituted quinolines, and the results
are listed in Scheme 1. Alkyl-substituted quinolines gave the
corresponding 1,2,3,4-tetrahydroquinolines in high yields
(2b−2e). Aryl-substituted quinolines and their derivatives
featuring electron-withdrawing as well as electron-donating
groups afforded the corresponding products in good to
excellent yields (2f−2p). Notably, functional groups such as
methoxy, fluoride, chloride, bromide, trifluoromethyl, and
dimethylamino on the aryl ring were well tolerated in the
reaction. The alkenyl groups, which are not directly attached to
the quinoline ring, were retained in the products (2d and 2n).
Moreover, compound 2e is a key intermediate in the synthesis
of ( )-galipinine, a natural product with multiple biological
activities.11 The reduction of quinolines containing a naphthyl
Figure 1. Reduction in water with Ag−H as the reducing species.
In addition, a ligand and a base were necessary for these works.
Herein, we report a ligand- and base-free reduction of
quinolines with Ag−H as the reducing species (Figure 1b).
Remarkably, the reduction proceeds smoothly in water under
air.
Water is one of the most ideal solvents for organic reactions,
and great advances have been made with respect to conducting
metal-catalyzed organic reactions in water.9 Because of the
unique physical and chemical properties, reactions proceeding
in water commonly result in unexpected reactivity and
selectivity in comparison with those performed in organic
solvents. Silver-catalyzed transformations in water have
witnessed increasing popularity due to the mild nature of
silver in many processes.8a,b,9i,10 These significant advances
Received: March 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01055
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 1. Reduction of C2-Substituted Quinolines
b
entry
[Ag]
[Si]H
solvent
yield of 2a (%)
c
1
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (5 mol %)
−
AgOTf (5 mol %)
AgOTf (5 mol %)
AgOTf (5 mol %)
AgOTf (5 mol %)
AgOAc (5 mol %)
Ag3PO4 (5 mol %)
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
Ph2SiH2
Ph3SiH
PMHS
DEMS
PhSiH3
PhSiH3
toluene
hexane
DCE
CHCl3
EtOH
H2O
H2O
H2O
H2O
H2O
trace
trace
nd
nd
98
98
97
nd
89
nd
nd
nd
95
c
2
c
3
c
4
5
6
7
8
9
10
11
12
13
14
H2O
H2O
H2O
H2O
93
a
Reaction conditions: 1a (0.25 mmol), [Ag] (10 mol %), [Si]H (1.0
mmol), in solvent (1 mL) at room temperature for 10 min under air.
Abbreviations: nd, not detected; PMHS, polymethylhydrosiloxane;
b
DEMS, diethoxymethylsilane. Determined by 1H NMR spectroscopy
c
using 1,3,5-trimethoxybenzene as an internal standard. At room
temperature for 2 h under air.
group as well as heteroaromatic groups proceeded smoothly to
give the corresponding products in 60−89% yields (2q−2u).
The quinoline was selectively reduced when employing a
pyridyl-substituted quinoline, and 2u was obtained in 60%
yield, although a higher reaction temperature was required.
When we subjected the C3-substituted quinolines to the
standard reaction conditions, only moderate conversions of the
starting material were observed. Moreover, quinolines with
other substitution patterns also gave similar results under the
conditions described above. We postulated that the inferior
reactivity of C3-substituted quinolines was caused by strong
coordination of the nitrogen atom to the Lewis acid silver(I)
center, effectively deactivating the catalyst. Such strong
coordination is hindered by bulky substituents in the C2
position on the quinoline ring, which prevents deactivation of
the catalyst.10a To our delight, further screening showed that
both increasing the reaction temperature and extending the
reaction time greatly enhanced the reactivity (for details of
these studies, see the Supporting Information). In this way, the
yield of 2w could be increased to 78% with an increase in the
reaction time to 10 h (at room temperature) and to 95% with
an increase in the reaction temperature to 95 °C (for a 5 h
reaction time, under an argon atmosphere). Subsequently, a
number of substituted quinolines were subjected to these two
sets of reaction conditions as shown in Scheme 2. With C3-
substituted quinolines, various substituents were well tolerated,
affording the desired products in moderate to good yields
(2v−2ab). Quinolines with other substitution patterns, such as
quinoline itself and 4-methylquinoline, also gave the
corresponding 1,2,3,4-tetrahydroquinolines in good yields
(2ac and 2aj). In the case of 6-substituted and 8-substituted
quinolines, methyl, chloride, and bromide groups were well
tolerated, and the corresponding products were isolated in
good yields (2ae−2ai). Although the presence of a hydroxyl
a
Reaction conditions: substrate (0.25 mmol), AgOTf (5 mol %),
PhSiH3 (1.0 mmol), in H2O (1 mL) at room temperature for 10 min
b
under air. Isolated yields; recovered substrates are given in
c
d
parentheses. For 10 h. The ratio was determined by 1H NMR
e
spectroscopy. At 50 °C for 30 min.
group dramatically decreased the conversion at room temper-
ature, desired product 2af was obtained in 64% yield at 95 °C.
The 2,3-disubstituted quinoline derivatives were then
surveyed, and the results are listed in Scheme 3. All the 2,3-
disubstituted quinolines reacted smoothly in 10 min at room
temperature, providing the corresponding disubstituted hydro-
genated products in good yields, with moderate to excellent
diastereoselectivities (Scheme 3, 4a−4f). Notably, the
reactions of 2-phenyl-3-alkyl-disubstituted quinolines (4a and
4b) afforded single trans-disubstituted products in high yields.
In addition, the high reactivity indicates that the presence of
bulky C3 substituents helped to prevent deactivation of the
catalyst. Gratifyingly, the reaction can be conducted on a gram
scale with 0.08 mol % loading of the catalyst, forming 2a in
72% yield with a turnover number of 900 (Figure S1).
A number of other N-heteroarenes were examined (Scheme
4). The protocol can be successfully applied to the reduction of
several aromatic heterocycles such as naphthyridine (5a), 1,10-
phenanthroline (5b), acridine (5c), and 2,3-dimethylquinoxa-
line (5d); albeit higher reaction temperatures and longer
reaction times are required. Surprisingly, the catalytic system
presented here was not able to facilitate the reduction of
isoquinoline to the hydrogenated N-heteroarene (6e), which
could be attributed to the strong coordination of isoquinoline
to Ag(I) (because the nitrogen is more accessible than in the
quinolines and C2-substituted quinolines) or the difficult
addition of the Ag−H species to isoquinoline. In addition,
B
DOI: 10.1021/acs.orglett.9b01055
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 2. Reduction of Quinolines with Various
Substitution Patterns
Scheme 4. Reduction of N-Heteroarenes
a b
,
a
Reaction conditions: substrate (0.25 mmol), AgOTf (5 mol %),
PhSiH3 (1.0 mmol), in H2O (1 mL) at the noted temperature for 30
b
c
min under air. Isolated yields. Recovered substrate 5d is given in
parentheses.
Control experiments were performed to understand the
reaction mechanism (Table S2 and Figure S2). As shown in
Table S2, no ligand effect was found in the reduction. The
hydrosilylation products were not observed in the reaction
system regardless of whether the water was replaced with
aprotic solvents (Figure S2a) or the amount of PhSiH3 was
decreased (Figure S2b). In addition, 3-silylated tetrahydroqui-
nolines gave only a trace amount of the desired products under
the standard conditions (Figure S2c). From these results, we
concluded that the reduction process was entirely different
from the Lewis acid-catalyzed reduction with silane as a
reductant, which usually undergoes a hydrosilylation proc-
ess,8f,13 and also recognized that water or alcohol was necessary
to initiate the reaction. When the reaction was conducted in
ethanol, PhSiH3 was converted to Ph(EtO)SiH2 or Ph-
(EtO)2SiH, each of which was identified by NMR analysis of
the final reaction mixture (Figure S2g). The result suggests
that alcohol acts as a ligand to promote the formation of silver
hydride12 along with a hydrogen source. The reaction of 1a
and 1v in d6-ethanol or D2O led to the product bearing 100%
and 91% deuterium at the third position, respectively (Figure
S2d,e). These observations suggest that the quinoline may be
reduced through a stepwise 1,4/1,2-addition of Ag−H species
to quinolines.8a−e Also, the addition of 2,6-di-tert-butyl-4-
methylphenol (BHT) had no obvious influence on the
conversion (Figure S 2f), confirming the silver-catalyzed
radical reduction process should be excluded.
a
Reaction conditions: substrate (0.25 mmol), AgOTf (5 mol %),
PhSiH3 (1.0 mmol), in H2O (1 mL) at room temperature for 10 min
b
under air. Isolated yields; recovered substrates are given in
parentheses. A. The reaction was performed at room temperature
for 10 min under air. B. The reaction was performed at room
temperature for 10 h under air. C. The reaction was performed at 50
c
d
e
f
°C for 30 min under air. D. The reaction was performed at 95 °C for
g
10 min under Ar. E. The reaction was performed at 95 °C for 5 h
under Ar.
a b
,
Scheme 3. Reduction of Disubstituted Quinolines
On the basis of the observations described above and
previous reports,13 an outer-sphere catalytic pathway involving
a stepwise 1,4/1,2-addition of the Ag−H species to quinoline,
which was activated by the Lewis acid Ag(I), was proposed
(Figure 2a, path B). Theoretically, in addition to pathway B as
described in Figure 2a, another possible pathway is a 1,2-
hydride addition followed by a 3,4-hydride addition (Figure 2a,
path A). To further clarify the active hydrogenation pathway,
the reductions of reaction intermediates 7a and 7c and their
analogue 7b were conducted under the standard conditions
(Figure 2b,c). The corresponding results suggest that the latter
process is most likely to be active in our catalytic system (for
the overall reaction mechanism, see Figure S3).
In summary, we have developed a practical silver-catalyzed
reduction of quinolines and electron-deficient N-heteroarenes
with hydrosilanes in water. The current protocol operates
under mild conditions and enables the reduction of quinolines
in good yields and selectivity in the absence of both a ligand
and a base. A high reaction efficiency (10 min) and ≤900
turnovers were achieved. Mechanistic studies indicate that the
reaction most likely proceeds through a stepwise 1,4/1,2-
a
Reaction conditions: substrate (0.25 mmol), AgOTf (5 mol %),
PhSiH3 (1.0 mmol), in H2O (1 mL) at room temperature for 10 min
b
c
under air. Isolated yields. The diastereomeric ratio (d.r) values were
determined by H NMR spectroscopic analysis.
1
pyridine also failed to give the desired hydrogenated product,
which may be for similar reasons.
C
DOI: 10.1021/acs.orglett.9b01055
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
(8) (a) Jia, Z.; Zhou, F.; Liu, M.; Li, X.; Chan, A. S. C.; Li, C.-J.
Angew. Chem., Int. Ed. 2013, 52, 11871−11874. (b) Liu, M.; Zhou, F.;
Jia, Z.; Li, C.-J. Org. Chem. Front. 2014, 1, 161−166. (c) Tate, B. K.;
Wyss, C. M.; Bacsa, J.; Kluge, K.; Gelbaum, L.; Sadighi, J. P. Chem. Sci.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01055.
́
2013, 4, 3068−3074. (d) Zavras, A.; Khairallah, G. N.; Krstic, M.;
Girod, M.; Daly, S.; Antoine, R.; Maitre, P.; Mulder, R. J.; Alexander,
Experimental procedures along with characterization
data and copies of NMR spectra (PDF)
̌
́
́
S.-A.; Bonacic-Koutecky, V.; Dugourd, P.; O’Hair, R. A. J. Nat.
Commun. 2016, 7, 11746. (e) Jia, Z.; Liu, M.; Li, X.; Chan, A. S. C.;
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Chem. Commun. 2006, 4104−4106.
AUTHOR INFORMATION
Corresponding Authors
■
(9) Selected reviews: (a) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35,
68−82. (b) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751−2772.
(c) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209−217.
(d) Simon, M. O.; Li, C.-J. Chem. Soc. Rev. 2012, 41, 1415−1427.
(e) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725−748.
(f) Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302−6337.
(g) Kostjuk, S. V.; Ganachaud, F. Acc. Chem. Res. 2010, 43, 357−367.
*E-mail: wangzk076@nenu.edu.cn.
*E-mail: bixh507@nenu.edu.cn.
ORCID
Zikun Wang: 0000-0002-8672-4311
Xihe Bi: 0000-0002-6694-6742
Notes
̈
(h) Lindstrom, U. M. Chem. Rev. 2002, 102, 2751−2772. (i) Li, C.-J.
Chem. Rev. 2005, 105, 3095−3165.
(10) (a) Liu, M.; Wang, H.; Zeng, H.; Li, C.-J. Sci. Adv. 2015, 1,
No. e1500020. (b) Yao, X.; Li, C.-J. Org. Lett. 2005, 7, 4395−4398.
(c) Jia, Z.; Li, X.; Chan, A. C.; Li, C.-J. Synlett 2012, 23, 2758−2762.
(11) (a) Houghton, P. J.; Woldemariam, T. Z.; Watanabe, Y.; Yates,
M. Planta Med. 1999, 65, 250−254. (b) Jacquemond-Collet, I.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Natural Science Foundation
of China (21871043, 21522202, 21502017, 21604082, and
21702028) and the Department of Science and Technology of
Jilin Province (20180101185JC and 20190701012GH).
́
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Benoit-Vical, F.; Valentin, A.; Stanislas, E.; Mallie, M.; Fouraste, I.
Planta Med. 2002, 68, 68−69.
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DOI: 10.1021/acs.orglett.9b01055
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