A one-pot process for the enantioselective synthesis of tetrahydroquinolines and tetrahydroisoquinolines: Via asymmetric reductive amination (ARA)

Article abstract of DOI:10.1039/c8cc03586e

Asymmetric reductive amination for the synthesis of both chiral tetrahydroquinolines (THQs) and tetrahydroisoquinolines (THIQs) has been realized with an Ir/ZhaoPhos catalytic system via a one-pot N-Boc deprotection/intramolecular asymmetric reductive amination (ARA) sequence. Control experiments reveal that HCl plays a vital role to the success of this transformation. The HCl acid assists the removal of the N-Boc protecting group and also provides chloride ions to interact with the thiourea moiety in ZhaoPhos, thus leading to excellent reaction enantiocontrol.

Full text of DOI:10.1039/c8cc03586e

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A One-Pot Process for the Enantioselective Synthesis of
Tetrahydroquinolines and Tetrahydroisoquinolines via
Asymmetric Reductive Amination (ARA)
Received 00th January 20xx,
Accepted 00th January 20xx
Tao Yang, Qin Yin, Guoxian Gu, and Xumu Zhang*,†
DOI: 10.1039/x0xx00000x
www.rsc.org/
chiral THQs or THIQs unit
Asymmetric reductive amination for the synthesis of both chiral
tetrahydroquinolines (THQs) and tetrahydroisoquinolines
(THIQs) has been realized with an Ir/ZhaoPhos catalytic system
via a one-pot N-Boc deprotection/intramolecular asymmetric
reductive amination (ARA) sequence. Control experiments
reveal that HCl plays a vital role to the success of this
transformation. The HCl acid assists the removal the N-Boc
protecting group and also provides chloride ion to interact with
the thiourea moiety in ZhaoPhos, thus leading to excellent
reaction enantiocontrol.
(1) direct asymmetric reduction of heteroarenes (well established)
∗
N
R
N
R
H
TM catalysis with H2
or
or
or
organocatalyzed
transfer
hydrogenation
∗
N
NH
R
R
(2) asymmetric reduction of cyclic imines (well established)
TM catalysis with H2
N
∗
NH
Chiral tetrahydroquinolines (THQs) and tetrahydroisoquinolines
(THIQs) are universal structural units in a large number of
biologically active molecules, including natural alkaloids and
pharmaceuticals.1 For instance, chiral 2-substituted THQ units exist
in naturally occurring (-)-angustrureine,2a (-)-galipinine2b and (-)-
cuspareine,2c and 1-substituted THIQ motifs are present in (+)-
cryptostyline II,2d drug molecule Solifenacin2e as well as an AMPA
receptor antagonist.2f Due to their significance, extensive efforts
have been devoted to the development of high efficient methods
toward chiral THQs and THIQs.
R
R
(3) one pot N-deprotection/intramolecular ARA (Chang, 2017)
NHBoc
R1
R1
1. TFA
∗
NH
O
2. [Ir]/(R)-SegPhos
H2, Ti(OiPr)4
R2
R2
up to 99% ee
19 examples
both THQs and THIQs
(4) one pot N-deprotection/intramolecular ARA for
O
R2
∗
R1
R2
N
H
R1
NHBoc
OMe
OMe
up to 98% ee
18 examples
O
N
N
1. HCl
2. [Ir]/ZhaoPhos, H2
N
Me
Me
Me
O
(-)-angustrureine
(-)-galipinine
(-)-cuspareine
MeO
MeO
NHBoc
R
MeO
MeO
R
CF3
∗
NH
O
N
N
Me
N
O
Ac
S
Ar
up to 98% ee
12 examples
Ar
O
F3C
N
H
N
H
N
MeO
Ph2P Fe
OMe
Cl
AMPA receptor antagonist
Ph2P
ZhaoPhos
(+)-cryptostyline II
Solifenacin
Fig. 1. Selected natural alkaloids and pharmaceuticals containing a
Scheme 1. Strategies toward chiral THQs and THIQs
Direct asymmetric reduction of easily accessed quinoline or
isoquinoline derivatives represents the most straightforward route to
achieve enantioenriched THQs and THIQs. To this end, transition
†
3
metal (TM) catalysis with molecular H2 and organocatalysis with
hydrogen transfer reagents have been well established (Eq 1, Scheme
1).4 TM-catalyzed asymmetric reduction of benzo-fused cyclic
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imines is an alternative strategy and several efficient catalytic and ZhaoPhos, however, with only moderate enantiocontrol (entry 1,
systems have been identified (Eq 2, Scheme 1)5. Besides, Table 1). We speculated that the poor asymmetric induction was due
intramolecular ARA,6 an approach which avoids the presynthesis of to a very weak interaction between the anion of TFA and the
the imines, provides another facile and efficient route towards chiral thiourea subunit in ZhaoPhos. TFA was thus replaced with HCl/Et2O
THIQs. Remarkably, based on Wills’s original contribution to remove the N-Boc protecting group. As expected, benefiting from
regarding a one-pot deprotection/cyclization/asymmetric transfer the strong anion bonding interaction between the thiourea moiety
hydrogenation for the synthesis of chiral amines,7a Chang recently and the chloride ion,9a,10 the asymmetric induction of the cyclization
unveiled an elegant one-pot N-Boc deprotection and Ir-catalyzed step enhanced remarkably, affording the desired product 2a with
ARA sequence for the preparation of chiral THIQs (Eq 3, Scheme 97% ee (entry 2). Commercially available chiral phosphine ligands
1).7b Despite remarkable advances, high efficient catalytic systems BINAP and SegPhos were also investigated, but both displayed
capable of furnishing both chiral THQs and THIQs remain rare and inferior results (entries 3-4). Screening of other solvents, such as
thus highly desirable.
THF, iPrOH, toluene and EtOAc, demonstrated that dichloromethane
remained the most efficient one (entries 5-8). In addition, rhodium
precatalyst proved to be also efficient, giving full conversions albeit
with slightly decreased enantiocontrol (entries 9-10). Further attempt
to use other HCl source did not provide superior results (entry 11).
Therefore, the optimal condition was identified as follows:
employing HCl/Et2O to remove the N-Boc protecting group,
[Ir(cod)Cl]2 and ZhaoPhos as the catalyst, and dichloromethane as
the solvent at 25 °C with a hydrogen pressure of 30 atm.
Recently we have developed a kind of novel ligand, ZhaoPhos,
comprising a chiral ferrocenyl bisphosphine scaffold and a tunable
thiourea subunit.8 By taking advantage of the anion bonding
interaction between the thiourea moiety in the ligand and chloride
counterion from the substrates, we have successfully realized the
asymmetric hydrogenation of unprotected NH imines,9a
isoquinolines and quinolones,9b as well as indoles.9c We envisaged
that in situ formed cyclic iminium ion, paired with a suitable
counteranion (such as Cl-), could be stereoselectively reduced
through similar working models (Eq 4, Scheme 1). We herein report
a unified strategy for asymmetric synthesis of both chiral THQs and
THIQs via a one-pot N-Boc deprotection and Ir-catalyzed ARA
sequence.
O
R2
(1) HCl/Et2O, DCM
R1
R2
N
H
R1
(2) [Ir(COD)Cl]2 (0.5 mol%)
ZhaoPhos (1.1 mol%)
DCM, H2 (30 atm), 25 oC, 24 h
NHBoc
1
2
Table 1. Optimization of Reaction Conditionsa
n
n
n
N
Me
N
C2H5
N
C3H7
N
C4H9
N
C5H11
H
H
H
H
H
2a 97% yield
97% ee
2e
95% yield
97% ee
2d
97% yield
97% ee
2b 95% yield
97% ee
2c 95% yield
96% ee
n
N
H
Me
n
MeO
Bn
N
H
Me
N
H
C7H15
N
H
N
H
C6H13
OMe
2f
2g
2h
2i
2j
96% yield
93% ee
95% yield
92% ee
94% yield
97% ee
94% yield
96% ee
96% yield
95% ee
Me
Br
Me
Br
N
O
N
Me
N
Me
N
Me
H
H
H
F
H
2k
2m
97% yield
95% ee
94% yield
98% ee
2n
96% yield
95% ee
2l 86% yield
97% eed
Br
N
N
N
H
N
H
H
H
OMe
F
F
F
2o 85% yield
2p 86% yield
2q 88% yield
2r 90% yield
80% ee
84% ee
85% ee
90% ee
a
1
Reaction conditions: (0.2 mmol), [Ir(cod)Cl]2 (0.5 mol%), ZhaoPhos (1.1 mol%), HCl (4.0 equiv.),
DCM (0.6 mL); bIsolated yield; cDetermined by HPLC; dDetermined by UPLC
Scheme 2. Substrate scope for the synthesis of chiral THQsa-c
With the optimal conditions in hand, the scope of the reductive
amination for the synthesis of chiral THQs was then studied, as
depicted in Scheme 2. Alkyl substituents (1b-1h) with various chain
lengths attached to the carbonyl moiety had only small influence to
the outcome of enantiocontrol, and excellent enantioselectivities of
the desired THQs were generally obtained (92-97% ee). Substituent
effect on the bridged benzene ring is not obvious in terms of
reactivity or enantioselectivity, and the enantiocontrol was excellent
throughout, regardless of the position and electronic property of the
substituents (2i-2n). Remarkably, a bromo-containing alkyl side
chain on the phenyl ring was well tolerated (2l). Besides alkyl
We began our study by exploring the reductive amination
conditions for the synthesis of chiral THQs with model substrate 1a.
Since the removal of the Boc protecting group on N atom is essential
to the subsequent cyclization, CF3COOH (TFA), as an obvious
choice, was first tried. With all volatile components removed, the
resulting mixture underwent smoothly asymmetric reductive
amination in the presence of a catalyst combination of [Ir(cod)Cl]2
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substituents, different aryl substituents attached to the carbonyl
To obtain insight into the efficacy of the catalytic system, L1 and
moiety were also investigated. In general, these substrates output L2 were tested under otherwise standard conditions, and the results
slightly inferior results regarding conversions and enantioselectivity were summarized in Table 2. The N-methylated ligand L1 displayed
(2o-2r, 80-90% ee).
comparable activity and slightly diminished enantiocontrol, possibly
due to the reason that there is only one acidic N-H proton available
to interact with the counterion (entry 2, 92% ee). Further, the ligand
L2 which has no thiourea subunit exhibited high activity but with
much worse asymmetric induction (entry 3, 55% ee). These results
suggest the importance of hydrogen bonds in this reaction and that
the thiourea motif could efficiently help to form a better chiral
environment.
Encouraged by the success towards the synthesis of chiral THQs
with Ir/ZhaoPhos catalytic system, we then copied the optimal
reaction conditions for the synthesis chiral THIQs. Unfortunately,
the reaction was totally shut down for 3a at the second step. We
were glad to find that addition of Ti(OiPr)4 over the reductive
amination step could overcome the obstacle.11 The ARA step of 3a
processed smoothly to give desired product 4a in a high yield albeit
moderate ee value (75% ee). Solvent effect was then evaluated to
improve the enantiocontrol, revealing that EtOAc was the optimal
solvent which afforded 4a with 94% yield and 93% ee (for details
see the Supporting Information).
Table 2. Investigation of Structure-Activity Relationship of
ZhaoPhos
To showcase the practicality of this protocol, TON experiments
were conducted. 1e was selected because its corresponding product
2e was a key intermediate to natural product angustureine.13
Although the transformation remained highly efficient with a
catalyst loading of 0.1 mol% (TON= 1000), further decrease of the
catalyst loading resulted in an obvious drop of the reactivity (94% to
40% yield, entries 1-5, Scheme 4).
Scheme 3. Substrate scope for the synthesis of chiral THIQsa-c
Under slightly revised reaction conditions, we explored the
generality of the protocol for the synthesis of chiral THIQs, as
summarized in Scheme 3. A variety of 1-aryl substituted THIQs
were effectively prepared with up to 98% ee and 95% yield (4a-4l).
The substituent position on both benzene rings of the THIQ has little
influence on the outcome of enantioselectivity. Notably, the
transformation went smoothly even with a catalyst loading of 0.2
mol% to efficiently give product 4a, a key intermediate to the drug
molecule Solifenacin2e and biologically active molecule (+)-
FR115427.12
Scheme 4. TON experiments of 1e
In summary, we have developed a highly efficient catalytic system
for asymmetric synthesis of both chiral THQs and chiral THIQs. The
strong Brønsted acid HCl plays a critical role in this transformation,
not only facilitating the removal the N-Boc protecting group, but
also providing chloride ion to interact with the thiourea moiety in
ZhaoPhos, thereby offering excellent enantiocontrol. Control
experiments revealed the superiority of ZhaoPhos against several
commercially available bisphosphine ligands.
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Asymmetric reductive amination for the synthesis of both chiral tetrahydroquinolines and
tetrahydroisoquinolines has been realized with an Ir/ZhaoPhos catalytic system via a one-pot
N-Boc deprotection/intramolecular asymmetric reductive amination (ARA) sequence.