Visible-Light Induction/Br?nsted Acid Catalysis in Relay for the Enantioselective Synthesis of Tetrahydroquinolines

Article abstract of DOI:10.1021/acs.orglett.9b01354

An efficient method merging Br?nsted acid catalysis with visible-light induction for the highly enantioselective synthesis of tetrahydroquinolines has been developed. This mild process directly transforms 2-aminoenones into 2-substituted tetrahydroquinolines with excellent enantioselectivities through a relay visible-light-induced cyclization/chiral phosphoric acid-catalyzed transfer hydrogenation reaction.

Full text of DOI:10.1021/acs.orglett.9b01354

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light Induction/Brønsted Acid Catalysis in Relay for the
Enantioselective Synthesis of Tetrahydroquinolines
Wenhui Xiong, Shan Li, Bo Fu, Jinping Wang,* Qiu-An Wang,* and Wen Yang*
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, People’s Republic of China
S
* Supporting Information
ABSTRACT: An efficient method merging Brønsted acid
catalysis with visible-light induction for the highly enantiose-
lective synthesis of tetrahydroquinolines has been developed.
This mild process directly transforms 2-aminoenones into 2-
substituted tetrahydroquinolines with excellent enantioselec-
tivities through a relay visible-light-induced cyclization/chiral
phosphoric acid-catalyzed transfer hydrogenation reaction.
Scheme 1. Catalytic Enantioselective Synthesis of
Tetrahydroquinolines
isible-light photocatalysis has emerged as a powerful
synthetic tool in modern organic chemistry.1 Merging
V
visible-light photochemistry with asymmetric catalysis for
efficient assembly of chiral molecules is an intriguing and
challenging field, and many successful catalytic systems have
been developed in the past decade.2 Among them, combining
achiral photosensitizers and chiral organocatalysts in cooper-
ative or relay catalysis has been widely regarded as an attractive
and efficient strategy. However, the majority of these binary
catalytic systems rely on chiral amines as organocatalysts for
the effective control of stereoselectivity.3 In contrast, catalytic
systems with other types of chiral organocatalysts (e.g.,
carbenes, thiourea, Brønsted acids) for asymmetric visible-
light photocatalysis have remained underdeveloped.4
Tetrahydroquinoline is an important structural unit
frequently found in many chiral pharmaceutical molecules
and natural alkaloids that exhibit diverse biological activities.5
Given their significance, chiral tetrahydroquinolines have
become an attractive synthetic target, and numerous catalytic
asymmetric methods have been established, especially for 2-
substituted ones.6 Among them, direct asymmetric hydro-
genation of quinolines offers the most straightforward and
convenient access to chiral tetrahydroquinoline derivatives and
has been well-explored by the development of various catalytic
systems (Scheme 1a).7 In addition, catalytic cascade reactions
with readily prepared simple starting materials have been
developed (Scheme 1b).8 For example, Gong and co-workers8a
reported an efficient tandem hydroamination/asymmetric
transfer hydrogenation reaction catalyzed by gold complex/
chiral phosphoric acid, transforming 2-(2-propynyl)aniline
derivatives into tetrahydroquinolines with excellent enantiose-
lectivities. Zhao’s group8c employed amino alcohols as
substrates and disclosed a highly enantioselective process
through borrowing hydrogen under the cooperative catalysis of
an achiral iridacycle and a chiral phosphoric acid. We
envisaged that the combination of visible-light induction and
chiral phosphoric acid catalysis may provide an efficient
catalytic system that could convert 2-aminochalcones9 into 2-
substituted tetrahydroquinolines through a relay photocycliza-
tion/asymmetric transfer hydrogenation reaction (Scheme 1c).
We started to test our hypothesis with 2-aminochalcone
(1a) as the model substrate and Hantzsch ester (HEH) as the
Received: April 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01354
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hydrogen source (Table 1). After trials, we found that the
combination of light from blue LEDs and chiral phosphoric
2). A range of 2-aminochalcones with different electron-
donating and -withdrawing groups reacted smoothly to afford
a
Table 1. Optimization of the Reaction Conditions
Table 2. Scope of the Enantioselective Synthesis of
Tetrahydroquinolines
a
b
c
entry
R1/R2 (in 2)
time (h) product yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph/H
36
36
15
120
36
12
18
18
18
40
12
40
24
18
48
12
36
36
60
48
22
22
2a
2b
2c
2d
2e
2f
2g
2h
2i
93
92
87
51
89
90
98
90
90
91
92
80
96
90
86
91
84
86
87
84
95
96
>99
99
97
95
99
4-MeC6H4/H
3-MeC6H4/H
2-MeC6H4/H
4-MeOC6H4/H
3-MeOC6H4/H
4-PhC6H4/H
4-FC6H4/H
4-ClC6H4/H
4-BrC6H4/H
3-BrC6H4/H
4-CF3C6H4/H
1-naphthyl/H
2-naphthyl/H
2-thienyl/H
2-furyl/H
b
c
entry
cat.
x
solvent
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
A
B
C
D
E
F
F
F
F
F
F
F
F
F
F
5
5
5
5
5
5
2
1
2
2
2
2
2
2
2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
toluene
THF
MeCN
EtOAc
EtOAc
EtOAc
12
12
12
12
12
12
24
36
24
24
24
24
24
48
36
>95
>95
>95
>95
>95
>95
95
80
>95
95
90
53
88
78
70
97
98
90
91
93
95
93
99
>99
>99
98
>99
>99
>99
98
99
99
87
98
83
84
81
89
98
98
93
90
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
10
11
12
13
>95
95
>95
95
d
17
Me/H
C6H5(CH2)2/H
Ph/6′-Cl
Ph/6′-Br
Ph/7′-Br
de
,
d
18
19
20
21
22
14
de
,
f
f
f
f
15
>95
a
Reactions were performed with 1a (0.10 mmol), Hantzsch ester
2u
2v
(0.35 mmol), and the catalyst in the solvent (1.0 mL), irradiated with
b
5 W blue LEDs. Determined by 1H NMR analysis, with 100%
Ph/7′-Ph
c
d
a
conversion for all reactions. Determined by HPLC analysis. Run
Reactions were performed with 1 (0.20 mmol), Hantzsch ester (0.60
mmol), and 2 mol % F in EtOAc (1.0 mL), irradiated with 5 W blue
e
with 0.30 mmol of Hantzsch ester. 0.2 M concentration.
b
c
LEDs. Yields of the isolated products. Determined by HPLC
analysis. Run in two steps. Run with 2 mol % catalyst A. Run in
d
e
f
acids could enable this transformation.10 In the presence of the
representative chiral phosphoric acid A (TRIP) and 5 W blue
LEDs, the cascade reaction proceeded cleanly in dichloro-
methane at room temperature to afford the desired
tetrahydroquinoline 2a with high efficiency and enantioselec-
tivity (entry 1). It is noteworthy that the reaction is metal-free
and requires no sensitizer. As far as we know, the majority of
catalytic systems for the synthesis of tetrahydroquinolines
involve metals, and removal of trace metals is usually a costly
and tedious process, especially in the pharmaceutical industry.
Subsequently, a series of chiral phosphoric acids B−F with
different substituents were screened, and catalyst F was the
best one, providing excellent enantioselectivity (entries 2−6).
Excellent enantioselectivity was maintained with 2 mol % F,
but further reducing the loading to 1 mol % decreased the
enantioselectivity and yield (entries 7 and 8). Variation of the
solvent had a limited impact on the outcome (entries 9−13).
Ethyl acetate was the solvent of choice, and other common
solvents all resulted in slightly diminished enantioselectivities.
Further study of the loading of HEH and the reaction
concentration identified the optimal conditions (3.0 equiv of
HEH and 0.2 M concentration) with excellent efficiency and
enantioselectivity (entries 14 and 15).
DCM.
the corresponding tetrahydroquinolines (2b, 2c, 2e−l, and 2s−
v) with high to excellent yields and enantioselectivities (90−
99% ee) (entries 2, 3, 5−12, and 19−22). The electronic
property of groups on the aromatic ring had a limited effect on
the outcome, while the steric hindrance of the R1 group greatly
affected the efficiency. 2-Aminochalcone 1d bearing a 2-methyl
group displayed much lower reactivity, and just a moderate
yield was achieved in a prolonged time (entry 4). 2-
Aminochalcones with 1-/2-naphthyl groups worked with
high efficiency, but the former gave lower enantioselectivity
(87% ee) (entries 13 and 14). 2-Aminoenones with
heteroaromatic and aliphatic groups were viable substrates,
providing the desired tetrahydroquinolines 2o−r in compara-
ble yields but with diminished enantioselectivities (81−89%
ee) (entries 15−18). The synthesis of 2,3-disubstituted
tetrahydroquinolines was also realized using the catalytic
method (Scheme 2). The 2,3-disubstituted tetrahydroquino-
line 2w was obtained in high yield with excellent
diastereoslectivity, and 2x was obtained in high yield but
78% ee. As shown in Scheme 3, a gram-scale catalytic reaction
was performed well with almost no erosion in the yield (90%)
and enantioselectivity (99% ee).
Having established the standard reaction conditions, we next
examined the substrate scope of the cascade reaction (Table
B
DOI: 10.1021/acs.orglett.9b01354
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Catalytic Enantioselective Synthesis of 2,3-
Disubstituted Tetrahydroquinolines
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.9b01354.
1
Experimental details, copies of H and 13C spectra of
new compounds, and HPLC chromatograms (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yangwen@hnu.edu.cn
*E-mail: wangqa@hnu.edu.cn
*E-mail: jinpingwang1985@126.com
Scheme 3. Gram-Scale Preparation
ORCID
Wen Yang: 0000-0002-3166-4171
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (Grant 21702055) and
the Youth Foundation of Hunan University (Grant
531107050885).
To understand the reaction mechanism, we carried out two
simple control experiments (Scheme 4). Under otherwise
Scheme 4. Control Experiments
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DOI: 10.1021/acs.orglett.9b01354
Org. Lett. XXXX, XXX, XXX−XXX