Enantioselective Synthesis of 4-Aminotetrahydroquinolines via 1,2-Reductive Dearomatization of Quinolines and Copper(I) Hydride-Catalyzed Asymmetric Hydroamination

Article abstract of DOI:10.1021/acs.orglett.9b02034

A 1,2-reductive dearomatization of quinolines and copper(II) acetate monohydrate/(R,R)-Ph-BPE/P(p-tolyl)₃-catalyzed enantioselective hydroamination sequence was developed, affording diverse 4-amino-1,2,3,4-tetrahydroquinolines with high levels of enantioselectivity in either a stepwise or one-pot fashion. Pleasingly, internal cis-cyclic alkenes, which are challenging substrates in copper hydride-catalyzed enantioselective hydroamination reactions, were transformed efficiently under mild conditions.

Full text of DOI:10.1021/acs.orglett.9b02034

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Synthesis of 4‑Aminotetrahydroquinolines via 1,2-
Reductive Dearomatization of Quinolines and Copper(I) Hydride-
Catalyzed Asymmetric Hydroamination
Qing-Feng Xu-Xu,† Xiao Zhang,*,† and Shu-Li You*,†,‡
†State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
‡Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China
S
* Supporting Information
ABSTRACT: A 1,2-reductive dearomatization of quinolines
and copper(II) acetate monohydrate/(R,R)-Ph-BPE/P(p-
tolyl)3-catalyzed enantioselective hydroamination sequence
was developed, affording diverse 4-amino-1,2,3,4-tetrahydro-
quinolines with high levels of enantioselectivity in either a
stepwise or one-pot fashion. Pleasingly, internal cis-cyclic
alkenes, which are challenging substrates in copper hydride-catalyzed enantioselective hydroamination reactions, were
transformed efficiently under mild conditions.
hiral tetrahydroquinolines (THQs) are widespread in
pharmaceuticals and natural products (Figure 1a).1 Their
the substrates and reduced products lead to potential
deactivation of the catalysts. In addition, installation of the
amine moiety on the quinoline is required prior to the
asymmetric transformation, which somehow renders this
protocol impractical. Considering the significant importance
of chiral amine-substituted THQs, as exemplified by 4-amino-
1,2,3,4-tetrahydroquinolines, which show various biological
activities, including CETP inhibition,4 NMDA receptor
antagonism,5 and potent bradykinin antagonism,6 the develop-
ment of a straightforward approach directly starting from
abundant quinolines is highly desirable.7
C
Reissert-type nucleophilic addition constitutes a commonly
used strategy for direct functionalization of quinolines and offers
a flexible choice to introduce functionalities such as nitrile,
alkyne, and so on (Figure 1b).8 However, to the best of our
knowledge, the engagement of amine moieties is problematic
and remains unknown to date. To circumvent the challenge, we
envisioned that an umpolung tactic using electrophilic amines
might be adopted. This hypothesis was inspired by pioneering
studies by the Buchwald group9a and the Hirano and Miura
groups,9b who seminally reported copper hydride-catalyzed
enantioselective hydroamination reactions independently in
2013. Since then, a series of chiral amines were obtained in good
to excellent yields, regioselectivities, and enantioselectivities
from readily available alkenes and alkynes.9−11 More recently,
our group disclosed that this powerful copper catalysis could be
extended to benzofurans, for which a benzofuran ring opening/
enantioselective hydroamination cascade was observed.9q On
the basis of the above considerations and continuing with our
interest in value-added functionalization of aromatic com-
Figure 1. Synthesis of chiral 1,2,3,4-tetrahydroquinolines via
dearomatization of quinolines.
efficient construction has long been a goal for both organic and
medicinal chemists.2 In addition to well-established cyclization
reactions such as the Pavarov reaction,1c dearomatization of
quinolines represents a straightforward and attractive method
toward these scaffolds. Notable examples include asymmetric
(transfer) hydrogenation and other reduction reactions (Figure
1b).3 Despite considerable progress, the enantioselective
incorporation of THQs with amine functionalities, which are
also ubiquitous components in natural products and drug
molecules, remains less explored.3k−m,o This might be attributed
to the fact that the strong coordination and poisoning capacity of
Received: June 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02034
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
ligand
conc. (M)
3
yield of 4aa (%)
ee of 4aa (%)
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L5
L5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.02
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3ab
3ac
3ac
3ac
3ac
3ac
3ac
33
72
59
6
42
18
57
14
80
12
84
84
86
87
87
87
88
88
89
90
87
95
20
93
32
78
83
85
85
87
94
88
92
75
L5 + PPh3
10
11
12
L5 + P(p-tolyl)3
L5 + P(p-tolyl)3
L5 + P(p-tolyl)3
L5 + P(p-tolyl)3
L5 + P(p-tolyl)3
L5 + P(p-tolyl)3
L5 + P(p-tolyl)3
L5 + P(p-tolyl)3
d
13
de
,
14
15
16
17
def
, ,
defg
, , ,
defh
, , ,
a
Reaction conditions: Cu(OAc)2 (5 mol %), ligand (5.5 mol %), secondary ligand (11 mol %, if used), 2a (0.20 mmol), 3 (0.24 mmol), and
(MeO)2MeSiH (0.8 mmol) in THF at 40 °C for 20 h. Catalyst was preprepared by mixing Cu(OAc)2, ligand and (MeO)2MeSiH together in THF.
b
c
d
e
f
Isolated yields. Determined by SFC analysis. 1.4 equiv of 3ac was used. Cu(OAc)2·H2O was used instead of Cu(OAc)2. The reaction was
g
h
carried out at room temperature. Cu(OAc)2·H2O (2.0 mol %), L5 (2.2 mol %), P(p-tolyl)3 (4.4 mol %). Cu(OAc)2·H2O (1.0 mol %), L5 (1.1
mol %), P(p-tolyl)3 (2.2 mol %), 48 h.
pounds, we explored whether copper hydride catalysis could
provide a general solution toward the synthesis of challenging
amine-substituted THQs with high enantioselective induction
(Figure 1c). Herein we report our results from this study.
At the outset, we envisioned that enantioselective hydro-
amination of quinolinium salts might be directly enabled by
copper hydride catalysis. However, the initial attempts all failed,
along with the observation that the starting materials remained.
This is largely due to the difficulties associated with resonance
stabilization caused by aromaticity. Inspired by the elegant
examples of stepwise reduction/enantioselective catalysis,12 we
therefore used a sequence as an alternative strategy, namely, 1,2-
reductive dearomatization of quinolines followed by copper
hydride-catalyzed asymmetric hydroamination of the resultant
1,2-dihydroquinolines. Nevertheless, this method would be very
challenging since the internal cis-cyclic alkenes are well-known as
challenging and problematic substrates in enantioselective
hydroamination catalyzed by copper hydride.11f
Upon treatment of 2a with 1.2 equiv of hydroxylamine ester 3aa
in a THF solution of CuH catalyst (obtained from Cu(OAc)2,
(R)-BINAP, and (MeO)2MeSiH, 0.5 M) at room temperature
for 20 h, the desired product 4aa was obtained in 33% yield with
42% ee (entry 1, Table 1). Encouragingly, after screening of
various ligands, we found that utilization of (R,R)-Ph-BPE (L5)
gave 4aa in 95% yield with 80% ee (entry 5, Table 1). Slightly
improved enantioselectivity was achieved when the substrate
was diluted to a concentration of 0.1 M (84% ee; entry 7, Table
1), but further decreasing the concentration resulted in a poor
yield (32%; entry 8, Table 1). Gratifyingly, the utilization of a
secondary ligand13 was found to be beneficial to the reaction,
and P(p-tolyl)3 provided the best results (87% ee; entry 10,
Table 1). Notably, different dibenzylamine precursors (3aa−ac)
exerted little impact on the reaction outcome (entries 11 and 12,
Table 1). 1-Adamantyl acid-derived hydroxylamine ester 3ac
was chosen as the reaction partner because of its slightly
improved efficiency and relatively ready availability and
cheapness. Further investigations of the substrate ratio, copper
source, reaction temperature, and catalyst loading were
conducted (entries 13−17, Table 1). It was identified that the
Accordingly, N-protected 1,2-dihydroquinoline 2a, synthe-
sized from quinoline (1a) via 1,2-reductive dearomatization, was
used as the substrate in the hydroamination reaction (Table 1).
B
DOI: 10.1021/acs.orglett.9b02034
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Organic Letters
Letter
reaction of 2a with 3ac (1.4 equiv) in the presence of Cu(OAc)2·
H2O (2 mol %), (R,R)-Ph-BPE L5 (2.2 mol %), P(p-tolyl)3 (4.4
mol %), and (MeO)2MeSiH (0.8 mmol) at room temperature
gave the best results (92% yield, 90% ee; entry 16, Table 1).
With the optimized conditions in hand, we next explored the
scope of 1,2-dihydroquinolines (Scheme 1). Various protecting
and 7-methyl substituted 1,2-dihydroquinolines were suitable
substrates, leading to the isolation of 4ua and 4va in 97% yield
with 84% ee and 78% yield with 85% ee, respectively.
Next, the amine electrophiles were examined. As illustrated in
Scheme 2, various nitrogen sources bearing varied benzylic
a b c
, ,
Scheme 2. Investigation of Amine Electrophiles
a b c
, ,
Scheme 1. Investigation of 1,2-Dihydroquinolines
a
b
Reaction conditions: as in entry 16 of Table 1. Isolated yields are
c
shown. The ee values were determined by HPLC or SFC analysis.
d
4-(N,N-Diethylamino)benzoic acid-derived hydroxylamine ester was
e
used. 1-Adamantanecarboxylic acid-derived hydroxylamine ester was
used. 2.0 equiv of 3 was used. Benzoic acid-derived hydroxylamine
f
g
ester was used.
a
b
moieties (4-ClC6 H4 CH2 −, 4-MeOC6 H4 CH2 −, 4-
PhC6H4CH2−, 2-BrC6H4CH2−, 2-thienylmethyl, 2-benzofur-
anylmethyl) were well-accommodated, delivering the corre-
sponding chiral tertiary amines (4ab−ag) in 46−94% yield with
91−92% ee. The reaction is also applicable to substrates 3h and
3i containing stereocenters adjacent to the nitrogen with
opposite configuration. The two diastereoisomers 4ah and 4ai
were obtained in 66% yield with 11:1 dr and in 71% yield with
18:1 dr, respectively, indicating that catalyst control process
operates. Interestingly, the cyclopropane motif, which is of
significance in drug discovery,14 could be introduced through
this hydroamination process (82% yield, 92% ee; 4aj). The
robustness of this reaction was further demonstrated by the
successful incorporation of morpholine and benzylamine on
THQs with excellent enantioselectivity (45% yield, 89% ee, 4ak;
48% yield, 92% ee, 4al).
Finally, we achieved the enantioselective construction of 4-
amino-1,2,3,4-tetrahydroquinolines directly from quinolines in a
one-pot fashion. However, the initial results were rather
disappointing, leading to the isolation of 4aa in 18% yield.
With modified reaction conditions (KBH4 was used for the 1,2-
reduction of quinolines), the results were significantly improved,
as shown in Scheme 3. The desired THQs were obtained in
satisfactory yields (55−90%) with good enantioselectivities
(87−90% ee). Notably, there is no need for isolation or
Reaction conditions: as in entry 16 of Table 1. Isolated yields are
c
shown. The ee values were determined by HPLC or SFC analysis.
d
20 h at rt and then 12 h at 40 °C.
groups on the nitrogen atom of the 1,2-dihydroquinoline, such
as −CO2Me, −CO2Et, −CO2 Bu, −CO2Bn, Fmoc, and −Ac,
i
were well-tolerated, and good to excellent yields (71−93%) and
enantioselectivities (82−90% ee) were achieved (4aa−fa).
However, the Ts group had a detrimental effect on the reactivity,
leading merely to the observation of recovered substrate 2g
(16% yield, 91% ee; 4ga). The reactions proceeded smoothly
with 1,2-dihydroquinolines bearing different substituents at the
6-position (−CO2Me, −CF3, −F, −Cl, −Br, −I, −Ph, 2-thienyl,
−Me, −OMe, −SMe), in all cases providing the corresponding
THQs in good yields (71−94%) with excellent enantioselectiv-
ities (87−92% ee) regardless of their electronic properties
(4ha−ra). Furthermore, substrates bearing a methyl substituent
at other positions were evaluated (4sa−va). Low conversion was
observed when the methyl group was incorporated at the 3-
position (25% yield, 93% ee, >19:1 dr; 4sa), while the reaction
was inhibited with a methyl group at the 4-position. These
decreased reactivities might be attributed to the unfavorable
steric hindrance encountered in the hydrocupration step. It was
remarkable to observe the formation of 4sa in a highly
enantioselective and diastereoselective fashion. As expected, 5-
C
DOI: 10.1021/acs.orglett.9b02034
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Organic Letters
Letter
a b c
, ,
were obtained in good to excellent yields with high
enantioselectivities. Importantly, this method represents a rare
example of highly enantioselective hydroamination of internal
cis-cyclic alkenes. Compatibility with gram-scale reaction and
versatile manipulations of the resultant THQs further enhance
the synthetic utility of the current method.
Scheme 3. One-Pot Synthesis
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02034.
a
Reaction conditions: 1 (0.5 mmol), ClCO2Me (0.6 mmol), and
KBH4 (0.5 mmol) were stirred at room temperature in MeOH (0.5
M) overnight. A solution of Cu(OAc)2·H2O (4.0 mol %), L5 (4.4 mol
%), P(p-tolyl)3 (8.8 mol %), (MeO)2MeSiH (1.0 mmol), and 3ac
(0.25 mmol) in THF (2.5 mL, 0.1 M) was added, and the reaction
Experimental procedures and analysis data for all new
compounds (PDF)
Accession Codes
b
c
CCDC 1903797 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, U.K.; fax: +44 1223 336033.
was continued at rt for 20 h. Isolated yields are shown. The ee
values were determined by HPLC or SFC analysis. 3.0 equiv of 1 was
used.
d
purification of the dihydroquinoline intermediate during the
process.
To our delight, the protocol was also amenable to scale-up and
diverse transformations. As shown in Scheme 4, the reaction of
AUTHOR INFORMATION
Corresponding Authors
■
Scheme 4. Gram-Scale Synthesis and Transformations of 4la
*zhangxiao@sioc.ac.cn
*slyou@sioc.ac.cn
ORCID
Shu-Li You: 0000-0003-4586-8359
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank MOST (2016YFA0202900), the National Natural
Science Foundation of China (21821002 and 21801248), the
Chinese Academy of Sciences (XDB20000000 and QYZDY-
SSW-SLH012), the Youth Innovation Promotion Association of
CAS (2019255), and the Shanghai Sailing Program
(18YF1428900) for generous financial support.
REFERENCES
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