Organocatalytic Atroposelective Friedl?nder Quinoline Heteroannulation

Article abstract of DOI:10.1021/acs.orglett.9b01731

An atroposelective Friedl?nder heteroannulation reaction of 2-aminoaryl ketones with α-methylene carbonyl derivatives has been developed for the first time with chiral phosphoric acid as an efficient organocatalyst. The desired enantioenriched axially chi

Full text of DOI:10.1021/acs.orglett.9b01731

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
̈
Organocatalytic Atroposelective Friedlander Quinoline
Heteroannulation
You-Dong Shao, Meng-Meng Dong, You-An Wang, Pei-Ming Cheng, Tao Wang,
and Dao-Juan Cheng*
Department of Chemistry and Chemical Engineering, Heze University, Heze 274015, People’s Republic of China
S
* Supporting Information
̈
ABSTRACT: An atroposelective Friedlander heteroannulation
reaction of 2-aminoaryl ketones with α-methylene carbonyl
derivatives has been developed for the first time with chiral
phosphoric acid as an efficient organocatalyst. The desired
enantioenriched axially chiral polysubstituted 4-arylquinoline
architectures were prepared with good to high yields and
enantioselectivities (up to 94% yield and up to 97% ee).
Furthermore, the products can be readily derivatized to afford an
array of new quinoline-containing heteroatropisomers, which hold great potential in asymmetric catalysis and drug discovery.
̈
uinolines and their derivatives have been tagged as
organocatalytic Friedlander reactions for the preparation of
Q “Privileged Scaffolds” owing to their widespread
quinolines with remote stereogenic centers have been
disclosed.6−8 On the other hand, axially chiral biaryl skeletons
are frequently encountered in many natural products, bioactive
compounds, and privileged chiral ligands and catalysts.9
Besides, atropisomerism plays an important role in controlling
the pharmacological properties of biological systems.10
Accordingly, considerable efforts have been devoted to the
search of efficient routes for the enantioselective construction
of various atropisomeric aryl−aryl or aryl-heteroaryl struc-
tures.11
appearance in natural and synthetic products that exhibit
remarkable pharmacological or physical properties (Figure
1).1−3 While numerous synthetic methods have been
Despite such significant advances, the enantioselective
synthesis of axially chiral quinoline-containing biaryl back-
bones, especially those by organocatalysis, remains rare. In
2016, the Zhou group realized an efficient kinetic resolution of
axially chiral 5- or 8-substituted quinoline derivatives via chiral
phosphoric acid (CPA) promoted asymmetric transfer hydro-
genation (Scheme 1a).12 Later, Matsubara, Asano and co-
workers developed a bifunctional organocatalytic aromatic
electrophilic halogenation reaction of prochiral 3-(quinolin-8-
yl)phenols to access 8-arylquinoline atropisomers (Scheme
1b).13 Surprisingly, the atroposelective formation of enan-
tioenriched 4-arylquinoline derivatives in an organocatalytic
and atom-efficient fashion from simple achiral substrates is
almost unexplored to date.14 Notably, 4-arylquinoline deriva-
tives show a wide spectrum of bioactivities. For example, the
HIV integrase inhibitor BI 224436 bearing a rotation inhibited
axis is being investigated to target the LEDGF/p75 binding
site15 and has recently been the first noncatalytic site integrase
inhibitor (NCINI) to advance into a phase Ia clinical trial.16
The dibenzo[c,f ][2,7]naphthyridine derivative represents a
potent phosphoinositide-dependent kinase-1 (PDK-1) inhib-
Figure 1. Selected privileged quinoline-containing natural product,
bioactive molecules, and chiral ligand.
̈
developed toward their synthesis, the Friedlander hetero-
annulation reaction, discovered over 135 years ago, is still one
of the most straightforward approaches to access polysub-
stituted quinolines.4 This transformation is generally accom-
plished through a condensation/cyclodehydration sequence
between 2-aminosubstituted aromatic carbonyl compounds
and α-methylene carbonyl derivatives in the presence of acidic
or basic catalysts.
In recent decades, organocatalysis has emerged as an
Received: May 16, 2019
important tool in organic synthesis.5 In this context, several
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Synthesis of Quinoline-Containing Heterobiaryl
Atropisomers
Table 1. Reaction Condition Optimization
b
c
entry
1
cat.
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1aa
1ba
(R)-C1
(R)-C2
(R)-C3
(R)-C4
(R)-C5
(R)-C6
(R)-C7
(R)-C8
(R)-C9
(R)-C10
(R)-C6
(R)-C6
(R)-C6
(R)-C6
(R)-C6
(R)-C6
(R)-C6
(R)-C6
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
THF
EtOAc
toluene
DCE
CHCl3
CHCl3
CHCl3
CHCl3
54
50
89
71
70
79
28
78
81
74
11
70
69
66
35
94
92
89
−5
−28
9
−17
−35
72
8
58
46
14
48
44
46
68
70
69
74
81
itor.17 Pitavastatin is a well tolerated and effective alternative
treatment for patients with hypercholesterolemia.18 Even the
structurally simple 4-phenyl chloroquinoline derivative CPQE
was demonstrated to be a promising antioxidant and
antidiabetic agent recently (Figure 1).19 Therefore, the design
and atroposelective construction of a new family of 4-
arylquinolines is highly appealing, yet still challenging. We
9
̈
posited that catalytic asymmetric Friedlander heteroannulation
10
11
12
13
14
15
16
reaction might allow a straightforward access to these valuable
heterobiaryl atropisomers.
̈
For a typical Friedlander heteroannulation, the 2,3-
substituted 4-aryl quinolines produced from corresponding 2-
aminoaryl ketones do not possess axial chirality because of the
low rotational barrier between the two aromatic rings (Scheme
1c). We envisioned that if Ar was an aryl bearing ortho-
substituents that could hinder the free rotation of the newly
formed aryl-quinoline bond, the resulting 4-arylquinolines
would be axially chiral. In order to reach this goal, the first task
we encountered is selection of a suitable chiral catalyst prompt
to efficiently promote the cascade process and induce axial
enantiocontrol. Guided by our ongoing interest in Brønsted
acid catalysis,20 we designed a chiral phosphoric acid (CPA)21
d
e
fgh
,
17 ,
18 ,
fg
a
Unless otherwise stated, all reactions were carried out with 2-
aminoaryl ketones 1 (0.10 mmol), ethyl acetoacetate 2a (0.30 mmol),
catalyst CPA (10 mol %) and solvent (1.5 mL) in sealed tube at 70
b
c
°C for 48 h. Isolated yield. Determined by chiral stationary phase
d
e
HPLC analysis. The reaction was run at 50 °C for 5 d. The reaction
f
was run at 100 °C. 5 Å molecular sieves (150 mg) were added.
g
h
̈
catalyzed asymmetric Friedlander heteroannulation reaction,
Glycine tert-butyl ester (10 mol %) was added. The reaction was
run for 24 h.
which provided an efficient route for the synthesis of
atropoisomeric 4-arylquinoline structures with good to high
yields and enantioselectivities (Scheme 1d).
Subsequently, various solvents were examined (Table 1, entries
11−14). Better results were observed with halogenated
solvents, and reactions in CHCl3 gave slightly higher
enantioselectivity.
We also studied the temperature profile of this reaction and
found that the atroposelectivity was slightly diminished at both
higher and lower temperatures (Table 1, entries 15−16; for
details on the catalyst and temperature screening, see
Supplementary Table S1). Further investigations on the
additives revealed that the addition of 10 mol % of a primary
amine, namely glycine tert-butyl ester, together with 5 Å
molecular sieves led to an evident acceleration on the reaction
rate without any negative effect on the enantioselectivity (92%
To validate our hypothesis, we first conducted the
̈
Friedlander heteroannulation reaction of (2-aminophenyl)-
(naphthalen-1-yl)methanone 1aa with ethyl acetoacetate 2a in
the presence of 10 mol % of BINOL-derived CPA (R)-C1 in
chloroform (CHCl3) at 70 °C. After a 48 h reaction time, the
desired axially chiral trisubstituted 4-aryquinoline 3aa was
obtained in 54% yield with 5% ee (Table 1, entry 1). To
improve the results, a series of chiral phosphoric acids with
different substituents and backbones were assessed (Table 1,
entries 2−10). Among them, SPINOL-derived catalyst (R)-C6
with a phenanthryl group was found to be the best in terms of
enantioselectivity (79% yield, 72% ee, Table 1, entry 6).
B
DOI: 10.1021/acs.orglett.9b01731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yield, 74% ee, Table 1, entry 17; for details on the additives
screening, see Supplementary Table S2).
(3be−3bj), and best results were obtained with a trifluor-
omethyl (3bi, 90% ee) or ester substituent (3bj, 91% ee).
Next, we evaluated the use of various aromatic amines
(Scheme 3) and found that the atroposelectivity of this
In view of the moderate result of the above model reaction
of (2-aminophenyl)(naphthalen-1-yl)methanone 1aa and the
significant influence of the ortho-substituents of the 4-aryl
group on the stereocontrol for the newly formed aryl-quinoline
bond, we exchanged the Ar group of 2-aminoaryl ketone from
1-naphthyl (1aa) to 2-methylphenyl (1ba). Gratifyingly, the
Scheme 3. Substrate Scope with Respect to 2-Aminoaryl
Ketones 1 and α-Methylene Carbonyl Derivatives 2
̈
Friedlander heteroannulation of 1ba with ethyl acetoacetate 2a
proceeded smoothly under the established optimal conditions
and afforded the axially chiral 4-aryquinoline 3ba in high yield
(89%) with improved enantioselectivity (81% ee). Replacing
the o-Me group with iPr or CF3 completely shut down the
reaction, whereas the others (Ph, Cl, Br, and CO2Et) led to
poorer enantioselectivity, indicating that the functional group
ortho- to the newly formed atropisomeric axis has a decisive
effect on the reaction outcome.22
Continuing with the 4-(o-tolyl)quinoline scaffold, we sought
out to explore a range of substitutions on the o-methyl phenyl
ring (Scheme 2). In general, adding substitution with different
Scheme 2. Substrate Scope with Respect to (2-
Aminophenyl)(o-tolyl)methanone 1b
a
Unless otherwise stated, all reactions were carried out with 2-
aminoaryl ketones 1 (0.10 mmol), α-methylene carbonyl derivatives 2
(0.30 mmol), catalyst (R)-C6 (10 mol %), glycine tert-butyl ester (10
mol %), and CHCl3 (1.5 mL) in sealed tube at 70 °C for 48 h. Yields
refer to isolated pure compounds. The ee was determined by chiral
b
stationary phase HPLC analysis. The reaction was performed at 1.0
c
mmol scale. The reaction was run at 90 °C for 96 h.
̈
catalytic asymmetric Friedlander reaction was very sensitive to
substitutions on the phenyl ring of the newly formed quinoline.
Compared with other positions (6- and 8-), higher
enantioselectivities were obtained with 7-chloro (3bo, 97%
ee) followed by 7-methyl (3bm, 96% ee) and 7-methoxy (3bn,
94% ee) substituted 4-arylquinolines. 2-Aminonaphthyl ketone
was also a competent substrate, furnishing axially chiral
benzo[g]quinoline derivatives with high optical purity (3br,
93% ee and 3bs, 91% ee). At this stage, we deduced that
installation of an appropriate substituent at the 7-position of
the newly formed quinolines might be able to improve the
enantioselectivity of other 4-arylquinolines. Pleasingly, adding
a chloro-substituent to the initial model substrate 1aa afforded
significantly improved enantioselectivity (3ab, 97% ee vs 3aa,
74% ee). A similar result was observed with 4-naphthylbenzo-
[g]quinoline 3ac (94%, 89% ee). Notably, these selectivities
were conserved when different o-halogenated substrates were
used, as exemplified by 3c and 3d, which contain a handle for
the postfunctionalization. It bears mentioning that the
a
All reactions were carried out with 2-aminoaryl ketones 1b (0.10
mmol), ethyl acetoacetate 2a (0.30 mmol), catalyst (R)-C6 (10 mol
%), glycine tert-butyl ester (10 mol %), and CHCl3 (1.5 mL) in a
sealed tube at 70 °C for 48 h. Yields refer to isolated pure compounds.
The ee was determined by chiral stationary phase HPLC analysis.
electronic properties at the ortho-, meta-, and para- positions of
the 2-methyl group had little effect on the reaction efficiency,
giving 3ba−3bk in good yields ranging from 70% to 89% and
moderate to high ee values (71−91%). What is worthy of note
is that incorporation of additional groups para- to the 2-methyl
group resulted in an evident increase in the enantioselectivity
C
DOI: 10.1021/acs.orglett.9b01731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
importance of the C7 position in 4-arylquinoline based drug
candidates on the serum shifted potency has been established
recently.16
tert-butyl ester additive), the axially chiral benzo[g]quinoline
3bw could be isolated in quantitative yield with 83% ee after
36 h (Scheme 5).
Further efforts were focused toward testing the compatibility
of various α-methylene carbonyl derivatives 2. The trans-
formation proceeded equally well with different alkyl
acetoacetates (3ad, 95% ee and 3ae, 96% ee). Variation of
the R2 group had a very strong influence on the reaction
results. Ethyl propionylacetate smoothly underwent the
reaction and provided product 3bt in good yield and selectivity
(80% ee). However, the reaction turned out to be very sluggish
for sterically demanding β-keto esters. An elevated reaction
temperature was required to achieve a better conversion. For
example, the 2-isopropyl 4-arylquinoline 3af was obtained in
an acceptable yield with a high ee value of 90% after being
heated at 90 °C for 4 days. However, utilizing ethyl
benzoylacetate resulted in a dramatic drop in ee value to
37% (3ag). Besides, several 1,3-diones, including acetylace-
tone, heptane-3,5-dione, and cyclohexane-1,3-dione, were all
tolerated in the catalytic process and afforded axially chiral
quinolines 3bu−3bw with good to high stereoselectivities
(76−92% ee). The absolute configuration of 3ab was assigned
to be (aS) by single-crystal X-ray analysis,23 and that of the
remaining products were assigned by analogy. We also tested
the configurational stability of the product by heating a
solution of (aS)-3ab in toluene at 100 °C for 48 h. Chiral
HPLC analysis showed that the ee was unaffected (see the
Supporting Information for details).
Scheme 5. Isolation of Intermediate and Control
Experiment
On the basis of the above experimental results, we propose
the following catalytic process (Scheme 6). The first step is
Scheme 6. Proposed Catalytic Cycle
Furthermore, the products can be readily derivatized to
afford an array of new quinoline-containing heteroatropisomers
(Scheme 4). The ester group in the chiral product 3ab could
Scheme 4. Synthetic Applications
condensation of the primary amine group in 2-aminoaryl
ketones 1 and 2 under promotion of CPA, leading to imine
intermediates 8, which then tautomerize to enamines 7. Then,
the intramolecular aldol reaction causes ring closure and gives
compounds 9, which finally lose water and furnish expected
quinoline products 3. It is obvious that CPA played an
important role in the asymmetric induction by creating a
suitable chiral environment in the cyclization step through
cooperative hydrogen bonding interactions. The observation
that adding a catalytic amount of achiral primary amine, such
as glycine tert-butyl ester, could accelerate the reaction to a
certain extent might be ascribed to the formation of imines
10,26 which was beneficial for the initial condensation to take
place.
be readily reduced by LiAlH4 at −20 °C or hydrolyzed with
NaOH in refluxed ethanol to produce the corresponding
axially chiral primary alcohol 4 and carboxylic acid 5 in high
yields, respectively, without the loss of enantiopurity. Treat-
ment of 3bi with m-CPBA led to a quantitative formation of
the quinoline N-oxide 6 with retained optical integrity.
Two fundamentally different mechanisms exist for the
̈
classical Friedlander reaction. While most of the evidence
favored the pathway involving the initial formation of the Schiff
base intermediate,24 a recent report has summarized that
̈
Friedlander reaction was initiated with an intermolecular aldol
In summary, we have developed the first organocatalytic
reaction under the typically used acidic or basic conditions.25
Fortunately, an evident byproduct was observed in the reaction
of utilizing 1,3-cyclohexanedione 2i as a substrate, which was
later demonstrated to be the enamine structure 7bw.26 When
7bw was subjected to the standard protocol (without glycine
atroposelective Friedlander heteroannulation reaction to
̈
assemble stereochemically stable enantioenriched polysubsti-
tuted 4-arylquinolines in high yields with good to excellent
enantioselectivities (up to 97% ee). The current study not only
expands the existing state of the art of N-heteroatropisomers
D
DOI: 10.1021/acs.orglett.9b01731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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(5) (a) Comprehensive Enantioselective Organocatalysis; Dalko, P. I.,
Ed.; Wiley-VCH: Weinheim, Germany, 2013. (b) Topics in Current
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Development of Organocatalysis. Nature 2008, 455, 304−308.
construction but also provides a useful avenue to access axially
chiral polysubstituted 4-arylquinoline scaffolds which might be
of significance for future biological and medicinal studies.
ASSOCIATED CONTENT
■
̈
(6) Li, L.; Seidel, D. Catalytic Enantioselective Friedlander
S
* Supporting Information
Condensations: Facile Access to Quinolines with Remote Stereogenic
Centers. Org. Lett. 2010, 12, 5064−5067.
(7) Ren, L.; Lei, T.; Gong, L.-Z. Brønsted acid-catalyzed
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01731.
̈
enantioselective Friedlander condensations: achiral amine promoter
plays crucial role in the stereocontrol. Chem. Commun. 2011, 47,
11683−11685.
Experimental procedures, NMR spectra, HPLC traces,
X-ray and analytical data (PDF)
́ ́
(8) Banon-Caballero, A.; Guillena, G.; Najera, C. Solvent-Free
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Enantioselective Friedlander Condensation with Wet 1,1’-Binaph-
thalene-2,2’-diamine-Derived Prolinamides as Organocatalysts. J. Org.
Chem. 2013, 78, 5349−5356.
Accession Codes
CCDC 1906249 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 emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(9) For some reviews: (a) Kozlowski, M. C.; Morgan, B. J.; Linton,
E. C. Chem. Soc. Rev. 2009, 38, 3193−3207. (b) Bringmann, G.;
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chengdaojuan0614@163.com.
ORCID
Dao-Juan Cheng: 0000-0001-7834-7563
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for the financial support from the National
Natural Science Foundation of China (Nos. 21602097 and
21601006).
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DOI: 10.1021/acs.orglett.9b01731
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