Iodine catalyzed reduction of quinolines under mild reaction conditions

Article abstract of DOI:10.1039/c8cc04262d

A reduction of quinolines to synthetically versatile tetrahydroquinoline molecules with I₂ and HBpin is described. In the presence of iodine (20 mol%) as a catalyst, reduction of quinolines and other N-heteroarenes proceeded readily with hydroboranes as the reducing reagents. The broad functional-group tolerance, good yields and mild reaction conditions imply high practical utility.

Full text of DOI:10.1039/c8cc04262d

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DOI: 10.1039/C8CC04262D
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Iodine Catalyzed Reduction of Quinolines under Mild Reaction
Conditions
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a,b
b
Chun-Hua Yang, Xixi Chen, Huimin Li, Wenbo Wei, ZhantaoYang * and Junbiao Chang *
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
reduction of quinolines to synthetically versatile the literature over the past few years. Recently, organoborane
tetrahydroquinoline molecules with I and HBpin is described. In such as tris(pentafluorophenyl)-borane (B(C ) and related
the presence of iodine (20 mol%) as a catalyst, reduction of Lewis acid analogues have been shown to be viable catalysts
2
6 5 3
F )
2
6,27
28,29
quinolines and other N-heteroarenes proceeded readily with for
hydroboranes as the reducing reagents. The broad functional- hydroboration
group tolerance, good yields and mild reaction conditions imply these advances, there are still drawbacks: 1) For
the
hydrogenation
,
hydrosilylation
and
3
0,31
of N-heteroaromatics (Scheme 1). Despite
high practical utility.
hydrogenation, the processes are typically operative at
elevated temperatures in glovebox. 2) For hydrosilylation and
hydroboration, these need an additional step of transfer-
hydrogenation reaction. In a search for a general and
operationally simple methodology, we would like report our
recent results on iodine-catalyzed reduction of quinolines
Tetrahydroquinoline derivatives are privileged structures in
pharmaceutical and agrochemical industries and for the total
1
,2
synthesis of natural products, for example, antibacterial
3
agent flumequine, torcetrapib,
4,5
tubulin polymerization
6
7
inhibitor,
AChE inhibitor
and antiarrhythmic drug
(Scheme 1).
8
nicainoprol (Figure 1). In addition, many natural alkaloids
MeO
F
MeO
2
C
CF
3
9
N
contain the tetrahydroquinoline unit, including angustureine,
1
N
3
F C
0-12
10-12
N
Me
galipinine,
and cuspareine.
Therefore, significant
MeO
MeO
O
CF
3
efforts have been made to develop efficient methods for the
1
construction of tetrahydroquinoline derivatives.
O
N
Et
3-15
COOH
COOEt
OMe
Tubulin polymerization inhibitor
Flumequine
Torcetrapib
Direct hydrogenation of quinolines is one of the most
straightforward and convenient methods to synthesize
NH
O
1
6-22
tetrahydroquinoline derivatives.
However, these processes
OH
N
O
H
N
N
O
are typically operative under high pressures (H ) and/or at
2
O
Bn
N
elevated temperatures, and they frequently require the use of
precious metals. From a synthetic point of view, such a
AChE inhibitor
Nicainoprol
tendency toward the complete reduction of quinolines with H2
OMe
OMe
O
O
N
N
N
certainly limits the opportunity for the synthesis of diverse
Me
Me
Me
alkaloids.
Angustrureine
Galipinine
Cuspareine
On the other hand, hydrosilanes and hydroboranes have been
Figure 1. Selected bioactive compounds containing 1,2,3,4-
utilized extensively as competent alternatives to H in catalytic
2
2
3-25
tetrahydroquinoline derivatives.
previous work
reduction chemistry.
Studies of the catalytic reduction of
quinolines with silane and borane reagents have appeared in
H
N
N
6 5 3
B(C F )
E
E-H, E=[Si] or [B]
proton donor
E=[Si] or [B] or H
this work
H
N
N
I
2
(20 mol%), HBpin
CH Cl , N , rt
R
R
2
2
2
Scheme 1. Catalytic reduction of N-heteroarenes with
hydrosilanes and hydroboranes.
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Very recently, Michael J. Ingleson reported the C2 borylation of substituent on the aryl groups also showed less effect on the
3
2
indoles using NHC-boranes and sub-stoichiometric I
Accordingly, number of literature reports have appeared showed less impact on the reaction. The electron-donating (2b-2l)
documenting the dramatic impact of additives such as I on and electron-withdrawing groups (2n-2v) on the aryl ring were well
Inspired by the literature tolerated, thus providing the tetrahydroquinolines in good yields.
2
as catalyst.
reaction. Electronic effects of the substituents on the aryl groups
a
2
1
8,19
hydrogenation of N-heteroarenes.
results, we thought that the borylation of quinoline would be For reactions with allyloxy-substituted quinoline, the quinoline ring
happened using iodine as catalyst. We initially chose HBpin as a was selectively reduced, thus generating the corresponding
boron agent, using 0.05 equiv. iodine as a catalyst in CH
2
Cl
2
.
tetrahydroquinoline 2k in 89% yield. The protocol was also
1
Monitoring of this reaction by H NMR spectroscopy revealed that compatible with quinolines bearing methoxy (1j), benzyloxy (1l),
C-H borylation was not happened. And 28% quinoline was fluoro (1n), chloro (1o) and bromo groups (1p) at the 8-position,
converted to tetrahydroquinoline. The reductive product was thus giving the products in good to high yields.
obtained in 20% yield upon silica gel chromatography. Encouraged
by this result, we next investigated the optimization of the reaction
conditions (Table 1). The amount of iodine was very crucial for the
reaction. The reduction of quinoline was not happened in the
absence of iodine (entry 1). However, fast reactions were observed
when the reaction was carried out at elevated amount of iodine,
and reaction could be completed in 24 h at room temperature in
the presence of 20 mol% iodine (entry 4). However, the reductive
product was not detected when iodine (1.0 equiv.) was used (entry
Table 2. Scope with respect to the quinolines.[a]
2 2 2
5). Hydrosilanes were then examined. When PhMe SiH and Ph SiH
were used, the reduction of quinoline was not happened (entry 6-7).
Dichloromethane was the most suitable solvent among the reaction
media tested (entry 8 - 11), and this reaction condition was used for
the study of other substrates.
[a]
Table 1. Optimization of reaction conditions.
[
b]
Entry
Catalyst (I
2
)
E-H (4.0 equiv.)
HBpin
Solvent
Yield (%)
[
c]
1
2
3
4
5
6
7
8
9
NO
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
nr
5 mol %
10 mol %
20 mol %
1.0 equiv.
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
HBpin
2
Cl
2
2
28
76
98
nr
HBpin
2
Cl
HBpin
2
Cl
2
2
[
[
[
c]
c]
c]
HBpin
2
Cl
PhMe
2
SiH
2
Cl
2
nr
2
Ph SiH
2
2
Cl
2
nr
HBpin
HBpin
HBpin
HBpin
THF
CH CN
24
80
40
78
3
[
a] Unless otherwise specified, all reactions were performed with
1
1
0
1
Hexane
Toluene
0.25 mmol substrate in 1 mL dichloromethane under argon
atmosphere. Yields are those of the isolated products. [b] Toluene,
1
00 °C. [c] 2.0 equiv. HBpin was used. [d] 6.0 equiv. HBpin was used.
[a] Unless otherwise specified, all reactions were carried out with Remarkably, it is well documented that functional groups such as
0
.25 mmol of 1a and 1 mL of solvent under argon atmosphere. [b] nitro group and ester were retained in the products 2r-2v.
1
Yields determined by H NMR analysis. [c] nr, no reaction.
With the optimized conditions (20 mol % Iodine, 4.0 equiv. of HBpin, corresponding product 2u in the presence of 4.0 equiv. HBpin over
CH Cl , rt, 24 h), the reactivity scope of quinolines was explored 48 h. When we reduced the amount of HBpin to 2.0 equiv., one
Table 2). As these results showed, the products could be obtained carbon–carbon double bond on the hetero-ring was retained, and
Interestingly, 8-nitroquinoline was efficiently converted to the
2
2
(
in good to high isolated yields. Quinolines bearing a methyl group 8-nitro-1,4-dihydroquinoline (2t) was obtained. In contrast, with 8-
underwent the reaction efficiently to give the products (2b−2h) in carbaldehydequinoline (1w), transfer hydrogenation of the
moderate to good yields (76−89%). And the position of the methyl carbaldehyde unit and quinoline ring occurred (2w). Moreover,
2
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when we subjected the substrate with a conjugated double bond through a same way as above. Intermediate H then can be
1x) to these reaction conditions, the double bond and the hydrolyzed to afford the final product 2a.
quinoline ring were all reduced. The synthetic utility of the present reduction was also explored
We next turned our attention to the reduction of N-heteroarenes (Scheme 4). The reaction of 6-methoxyquinoline (1i) was performed
Table 3). The reactions of isoquinoline (3a), acridine (3b), 1,10- successfully on a gram scale (1.59 g, 10 mmol) to give a 85% yield of
(
(
phenanthroline (3c), and quinoxaline (3d) all proceeded readily.
product 2i, and subsequent N-amidation delivered the tubulin
polymerization inhibitor (6-methoxy-3,4-dihydroquinolin-1(2H)-
yl)(3,4,5-trimethoxyphenyl)methanone (6) in 90% yield (Scheme 4a).
Moreover, 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (2y) can
[a]
Table 3. Scope with respect to other N-heteroarenes.
1
9
be converted into flumequine . As a specific synthetic application,
we developed a formal synthesis of galipinine, a natural product
with multiple biological activities. Preparation of 2-(2-
[
a] The reaction was carried out with 0.25 mmol substrate, 1 mmol (benzo[d][1,3]dioxol-5-yl)ethyl)-1,2,3,4-tetrahydroquinoline
HBpin, 20 mol % Iodine and 1 mL CH Cl under argon atmosphere at through two steps including formation of carbon-carbon double
room temperature. Yields are those of the isolated products.
bond and reduction with I and HBpin, which can be converted into
NMR experiments were carried out to study the interaction galipinine (Scheme 4b).
between I , quinoline 1a and or HBpin. The NMR results indicated
that a complex of quinoline and I
interaction between I and HBpin.
(9)
2
2
2
2
2
2
3
3
2
was formed. There was also an
2
In order to understand the hydrogen in the transformations,
deuterium-labeled experiments were carried out with 1a. When the
reaction system of 1a was added D
2
O，deuterated product 2a’ was
O is also H-donor
obtained. This result clearly demonstrated that D
2
4-36
3
for the hydrogenation reaction via DOBpin.
This result is
consistent with the NMR experiments (supporting information).
Scheme 2. Deuterium-labeled experiments
On the basis of previously reported results and these preliminary
studies, we propose a possible reaction pathway for the reduction
of quinolines in Scheme 3.
Scheme 4. Applications of synthesized 1,2,3,4-tetrahydroquinoline
derivatives.
In summary, the first catalytic reduction of quinolines with I
HBpin is reported. This scalable method efficiently generates
,2,3,4-tetrahydroquinoline derivatives in one synthetic step. The
2
and
1
suitability in the reduction of other N-heteroarenes has also been
demonstrated. The broad functional-group tolerance, good yields
and mild reaction conditions make this transformation an attractive
method for the synthesis of tetrahydroquinoline derivatives which
are valuable building blocks in synthesis.
Conflicts of interest
There are no conflicts to declare.
Scheme 3. Proposed mechanism.
When I
complex A was formed.
hydride transfer from HBpin to A through I → B interaction (B) and
2
was mixed with the substrate quinoline 1a, a molecular
Notes and references
3
3
The complex A could facilitate the
1
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DOI: 10.1039/C8CC04262D
Title
Iodine Catalyzed Reduction of Quinolines under Mild Reaction Conditions
Authors
a
a
a
a
a,b
b
Chun-Hua Yang, Xixi Chen, Huimin Li, Wenbo Wei, ZhantaoYang * and Junbiao Chang *
Affiliations
a Department Henan Province Key Laboratory of New Opto-electronic Functional Materials, College
of Chemistry and Chemical Engineering, Anyang Normal University, 436 Xian’ge Road, Anyang
455000, P. R. China
b School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China
Acknowledgements
We acknowledge financial support from the National Natural Science Foundation of China
(81703353), China Postdoctoral Science Foundation (2017M612421, 2018T110744) and National
Natural Science Foundation of Henan Province (182300410295).

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H
N
• broad functional-group tolerance
N
I2 (20 mol%), HBpin
CH2Cl2, N2, rt
•
good yields
• mild reaction conditions
wide application
R
R
2
•
8 examples
up to 93% yield