Catalytic Asymmetric Synthesis of Atropisomeric Quinolines through the Friedl?nder Reaction

Article abstract of DOI:10.1055/s-0039-1690228

A phosphoric acid catalyzed atroposelective Friedl?nder reaction was developed in which acetylacetone and a variety of 2′-substituted 2-Aminobenzophenones were successfully employed to give optically active biaryl quinolines in good yields and with high enantioselectivities.

Full text of DOI:10.1055/s-0039-1690228

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
J. Wan et al.
Letter
Synlett
Catalytic Asymmetric Synthesis of Atropisomeric Quinolines
through the Friedländer Reaction
Junlin Wana
Hongxin Liua,b
CPA :
i-Pr
i-Pr
Yunjun Lan†a
Xinhua Lia
Xingena Hua
Juan Lia
Hong-Ping Xiaoa
N
NH2
O
R2
R1
i-Pr
O
O
CPA (10 mmol%)
PhCN, 5 Å MS, 20 h
17 examples
O
O
+
P
R1
OH
R2
O
O
i-Pr
R
1 = halo, alkyl, trifluoromethyl
R2 = alkyl
up to 94% yield
up to 95% ee
Jun Jiang*a
0
0
0
0-0
0
0
1-
5
8
1
5-1
6
0
0
i-Pr
i-Pr
a College of Chemistry and Materials Engineering,
Wenzhou University, Wenzhou, Zhejiang Province
325035, P. R. of China
junjiang@wzu.edu.cn
b Institute of New Materials and Industrial Technology,
Wenzhou University, Wenzhou, 325035,
P. R. of China
Received: 05.10.2019
Accepted after revision: 13.10.2019
Published online: 05.11.2019
formations. Although many contributions have been made
to the catalytic asymmetric syntheses of axially chiral biaryl
compounds, the direct catalytic construction of a quinoline
motif with simultaneous creation of atroposelectivity,
which might provide versatile atropoisomeric quinolines
from simple starting materials, is an attractive target that
remains largely unexplored and unexploited.12 We sur-
mised that a Friedländer reaction, an efficient cascade ap-
proach to polysubstituted quinolines from 2-aminobenzo-
phenones and 1,3-dicarbonyl compounds, might be an ideal
way of achieving this goal.
DOI: 10.1055/s-0039-1690228; Art ID: st-2019-l0450-l
Abstract A phosphoric acid catalyzed atroposelective Friedländer re-
action was developed in which acetylacetone and a variety of 2′-substi-
tuted 2-aminobenzophenones were successfully employed to give opti-
cally active biaryl quinolines in good yields and with high
enantioselectivities.
Key words Friedländer reaction, atroposelectivity, quinolines, phos-
phoric acids, acetylacetone
O
Since the first detection of atropisomerism by Christie
and Kenner in 1922,1 axially chiral scaffolds, especially bi-
aryl ones, have been found in numerous natural products,
bioactive compounds, functional materials, chiral catalysts,
and ligands (Figure 1).2–5 Inspired by these findings, many
groups have since explored the asymmetric synthesis of ax-
ially chiral biaryl compounds.6 In this context, asymmetric
C–H functionalization reactions provide efficient strategies
for constructing these molecules from prepared heteroar-
yls.7 Furthermore, organocatalytic constructions of axially
chiral biaryl compounds through transfer hydrogenation,8
electrophilic halogenation,9 or annulation10 have also be-
come well established. These reported examples provide
various approaches for obtaining diverse axially chiral bi-
aryl compounds with good outcomes. As part of our con-
tinuing interest in the catalytic asymmetric synthesis of
heterocycles,11 we are particularly interested in quinoline-
type chiral biaryl moieties, not only because these repre-
sent important key structures of alkaloids and bioactive
compounds, but also because of their unique properties,
such as coordination and basic properties in catalytic trans-
N
N
N
O
t-Bu
PPh2
X
N
CO2H
t-Bu
X = PPh2 or NHR
Ligands I
BI 224436
HIV integrase inhibitor
Ligand II
Figure 1 Bioactive compound and ligands with axially chiral biaryl
structures
A simple retrosynthetic analysis clearly indicated that
2′-substituted 2-aminobenzophenones might be suitable
reactants to provide restricted rotation of the two aromatic
rings in the products of the Friedländer reaction. However,
few examples exist of enantioselective Friedländer reac-
tions, all of which were focused on breaking the symmetry
of 4-substituted cyclohexanes.12,13 Here, we report a chiral
phosphoric acid catalyzed atroposelective Friedländer reac-
tion of acetylacetone with a variety of 2-substituted benzo-
phenones that affords enantioenriched biaryl quinolones in
good yields and with high enantioselectivities.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Wan et al.
Letter
Synlett
To test our hypothesis regarding the chiral-acid-cata-
lyzed atroposelective Friedländer reaction, (2-aminophe-
nyl)(2-{2-[4-(trifluoromethyl)phenyl]ethyl}phenyl)metha-
none (1a) and acetylacetone (2) were treated under various
conditions (Table 1). First, the catalytic activity of various
chiral phosphoric acids Cat.1–Cat.7 was evaluated in CHCl3.
Most phosphoric acids promoted the target reaction well
and afforded the desired product 4a in moderate to good
yields and enantioselectivities (Table 1, entries 1–7), ac-
companied by small amounts of the enamine intermediate
3a. The 2,4,6-triisopropylphenyl-substituted catalyst Cat.5
proved to be the catalyst of choice (entry 5; 65% yield, 84%
ee). In addition, Cat.8,14 a novel Brønsted acid with low pH,
was also tested. However, this showed poor catalytic ability,
and none of the Friedländer reaction product was obtained
(entry 8). Subsequently, the effect of the solvent was stud-
ied and it was found that both the reactivity and enantiose-
lectivity were improved by employing PhCN as the reaction
medium. Finally, the best result was obtained when the re-
action was carried out in the presence of 5 Ǻ molecular
sieves while heating from rt to 120 °С (Table 1, entry 15;
92% yield, 88% ee).
Table 1 Effects of Various Conditions on the Reaction of the 2-Aminobenzophenone 1a and Acetylacetone (2)a
N
NH
O
O
NH2
O
O
F3C
Cat.
+
+
F3C
O
F3C
solvent, temp.
O
1a
2
3a
4a
Ar
i-Pr
i-Pr
O
O
O
O
O
P
OH
O
O
O
O
Ar
H
O
(R)-Cat.1: Ar = 1-naphthyl
(R)-Cat.2: Ar = 2,4,6-trimethylphenyl
(R)-Cat.3: Ar = 1-pyrenyl
O
i-Pr
O
O
(R)-Cat.4: Ar = 4-(2-naphthyl)phenyl
(R)-Cat.5: Ar = 2,4,6-triisopropylphenyl
(R)-Cat.6: Ar = triphenylsilyl
(R)-Cat.7: Ar = phenyl
i-Pr
Cat.8
Entry
Catalyst
Solvent
Yieldb (%) of 3
Yieldb (%) of 4
eec (%)
1
2
(R)-Cat.1
(R)-Cat.2
(R)-Cat.3
(R)-Cat.4
(R)-Cat.5
(R)-Cat.6
(R)-Cat.7
Cat.8
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
toluene
THF
8
trace
11
8
45
72
31
60
65
trace
46
–
5
26
13
16
84
–
3
4
5
trace
12
6
6
7
18
–
8
18
5
9
(R)-Cat.5
(R)-Cat.5
(R)-Cat.5
(R)-Cat.5
(R)-Cat.5
(R)-Cat.5
(R)-Cat.5
56
60
52
46
68
83
92
84
82
75
70
88
88
88
10
11
12
13
14e
15e,f
trace
–
CPMEd
PhCN
PhCN
PhCN
–
–
–
–
a Unless otherwise noted, the reactions were carried out with 1a (0.1 mmol), 2 (0.5 mmol), and catalyst (10 mol%) in solvent (0.5 mL) at 80 °C for 1 d.
b Isolated yield.
c Determined by chiral HPLC.
d Cyclopentyl methyl ether.
e At rt for 12 h then 120 °С for 8 h.
f 5Å MS (50 mg) was added.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

C
J. Wan et al.
Letter
Synlett
The scope of the protocol was fully evaluated by em-
ploying a variety of 2′-substituted 2-aminobenzophenones
under the optimized reaction conditions.15 As shown in
Scheme 1, we first studied the influence of substituents on
ring 1. We found that benzophenones with an electron-
withdrawing or electron-donating group on the 4-position
of ring 1 afforded the desired products 4b–f in good yields
and 92–95% ee (Scheme 1), whereas substitution at the 5-
position of ring 1 resulted in an obvious decrease in the en-
antioselectivity (4g and 4h). Next, the effect of substituents
on the 2′-position of ring 2 was evaluated. Benzophenones
bearing various arylethyl groups on the 2′-position reacted
smoothly with acetylacetone to give biarylquinolones 4l–p
containing four aromatic rings in high yields (76–94%) and
high optical purities (86–95% ee). Additionally, propyl- or
isopropyl-substituted benzophenones proved to be good
participants in this transformation and were converted into
the corresponding products 4q and 4r with good results.
Subsequently, other 1,3-dicarbonyl compounds were also
examined under the standard reaction condition, but no
satisfactory results were obtained.
N
R1
2
NH2
1
O
R2
2'
2
(R)-Cat.5
O
O
1'
3
3'
4'
R2
O
R1
+
2
1
5
5 Å MS, PhCN, rt to 120 °C, 20 h
1
6
4
6'
5'
1
2
4
N
F
N
MeO
N
F3C
N
O
O
O
O
CF3
CF3
CF3
CF3
4b
4c
4d
4e
82% yield, 93% ee
87% yield, 93% ee
60% yield, 92% ee
84% yield, 95% ee
Cl
N
N
MeO
MeO
N
Cl
N
Cl
O
O
O
O
Bn
CF3
CF3
CF3
4f
4g
4h
4i
85% yield, 95% ee
86% yield, 95% ee
88% yield, 76% ee
62% yield, 88% ee
Cl
N
N
Cl
N
Cl
N
Cl
N
O
O
O
O
O
F
F
F
F
Ph
CN
Cl
OMe
F
4j
82% yield, 95% ee
4k
4l
4m
4n
94% yield, 86% ee
79% yield, 95% ee
86% yield, 94% ee
89% yield, 94% ee
Cl
N
Cl
N
Cl
Cl
N
Cl
N
O
O
O
O
O
Cl
4o
76% yield, 93% ee
4p
4q
88% yield, 92% ee
4r
83% yield, 90% ee
81% yield, 93% ee
Scheme 1 Chiral phosphoric acid catalyzed asymmetric Friedländer reaction of 2′-substituted 2-aminobenzophenones 1 with acetylacetone (2).
Reagents and conditions: 1 (0.1 mmol), 2 (0.5 mmol), (R)-cat.5 (10 mol%), PhCN (0.5 mL), rt, 12 h then 120 °С, 8 h. Isolated yields are reported; enantio-
selectivities were determined by chiral HPLC.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

D
J. Wan et al.
Letter
Synlett
O
OH
KBH4
+ diastereomer
45%
Cl
MeOH, rt
N
Cl
N
4q
5
92% ee
48% yield, 91% ee
X-ray structure for 5
Scheme 2 Simple transformation of Friedländer reaction product
N
To demonstrate the synthetic utility of our method, a
simple transformation of a Friedländer reaction product
was carried out (Scheme 2). Product 4q was reduced by
KBH4 in MeOH at room temperature, to give the corre-
sponding biarylquinoline-type alcohol 5 in 93% yield and
with high enantioselectivity (49:51 dr; 91% ee). The stereo-
chemistry of 5 was assigned as (S,R) by X-ray crystal struc-
ture analysis (see Supporting Information).16
Next, a gram-scale asymmetric Friedländer reaction
was also performed. As shown in Scheme 3, treatment of 1q
(1 g, 3.65 mmol) with 2 under the optimal reaction condi-
tions gave the desired product 4q in good yield (83%) with
maintained enantioselectivity (91% ee).
NH2
O
R
O
O
O
O
+
P
*
R
O
OH
Cat.5
O
1
2
4
H
O
N
R
N
H
*
O
O
P
O
O
O
O
H
R
O
I
O
P
H
O
O
O
III
H
N
O
O
P
O
O
O
H
O
R
II
O
NH2
Scheme 4 Proposed mechanism of the chiral-phosphoric-acid-cata-
lyzed asymmetric Friedländer reaction between 2-aminobenzophe-
nones 1 and acetylacetone (2).
O
O
O
(R)-Cat. 5 (10 mmol%)
+
PhCN, 5 Å MS, 20 h
Cl
N
Cl
1q
2
4q
83% yield, 91% ee
3.65 mmol, 1.0 g
Scheme 3 A gram-scale Friedländer reaction
Supporting Information
Supporting information for this article is available online at
On the basis of the results obtained above, we proposed
the mechanism shown in Scheme 4 for the chiral phosphor-
ic acid catalyzed atroposelective Friedländer reaction. In
the promotion by the phosphoric acid Cat. 5, the 2-amino-
benzophenone 1 condenses with acetylacetone (2) to afford
an imine intermediate I, which is then converted into the
nucleophilic enamine intermediate II. Subsequently, a
phosphoric-acid-catalyzed intramolecular aldol reaction
gives a dihydroquinoline bearing a tertiary alcohol in enan-
tioenriched form. Finally, the resulting dihydroquinoline
eliminates a molecule of H2O to produce the desired atro-
poisomeric quinolines 4 in good yield and with high enantio-
selectivity.
https://doi.org/10.1055/s-0039-1690228.
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References and Notes
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Funding Information
(4) (a) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew.
Chem. Int. Ed. 2009, 48, 6398. (b) LaPlante, S. R.; Edwards, P. J.;
Fader, L. D.; Jakalian, A.; Hucke, O. ChemMedChem 2011, 6, 505.
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We are grateful for financial support from the National Natural Sci-
ence Foundation of China (NSFC, Grant Nos. 21573161 and
21571144), the Natural Science Foundation of Zhejiang Province
(Grant Nos. LY18B020011 and LQ19B020004), and the Foundation of
Wenzhou Basic Scientific Research Project (G20180015).
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© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

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(15) Phosphoric-Acid-Catalyzed Asymmetric Friedländer Reac-
tion; General Procedure
A Schlenk tube was charged with the appropriate 2-aminoben-
zophenone 1 (1 equiv, 0.1 mmol), acetylacetone (2; 5 equiv, 0.5
mmol), catalyst Cat.5 (0.1 equiv, 10% mmol), powdered 5 Å MS
(50 mg), and anhyd PhCN (0.5 mL). The resulting mixture was
stirred at rt for 12 h and then at 120 °С for an additional 8 h.
When the reaction was complete, the mixture was purified by
flash column chromatography [silica gel, PE–EtOAc (8:1 to 6:1)].
1-[2-Methyl-5-(3-{2-[4-(trifluoromethyl)phenyl]ethyl}phe-
nyl)quinolin-3-yl]ethanone (4a)
Yellow liquid; yield: 39.9 mg (92%; ee 88%); []D27 +5.6 (c 0.01,
EtOAc). HPCL [Daicel Chiralpak AD-H, hexane–i-PrOH (98:2),
flow rate: 0.7 mL/min,  = 254 nm, 25°С]: tR (major) = 11.40
min; tR (minor) = 12.42 min. 1H NMR (500 MHz, CDCl3):  = 8.09
(d, J = 8.4 Hz, 1 H), 7.76–7.68 (m, 1 H), 7.46 (t, J = 7.3 Hz, 1 H),
7.42–7.32 (m, 5 H), 7.25 (d, J = 9.4 Hz, 1 H), 7.19 (d, J = 7.4 Hz, 1
H), 6.89 (d, J = 8.0 Hz, 2 H), 2.81–2.60 (m, 2 H), 2.71 (s, 3 H),
2.66–2.60 (m, 1 H), 2.56–2.49 (m, 1 H), 2.08 (s, 3 H). 13C NMR
(126 MHz, CDCl3):  = 205.01, 153.54, 147.37, 145.26, 143.11,
139.86, 135.16, 134.42, 130.22, 130.08, 129.38, 129.28, 128.93,
128.53, 126.62, 126.23, 125.98, 125.46, 125.20, 125.17, 125.14,
125.11, 36.10, 34.64, 31.90, 23.85. HRMS (Bruker micrOTOF-
QII): m/z [M + H]+ calcd for C27H23F3NO: 434.1726; found:
434.1743.
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nyl]ethyl}phenyl)quinolin-3-yl]ethanone (4b)
Yellow liquid; yield: 38.9 mg (87%; ee 93%); []D27 +16.4 (c 0.01,
EtOAc); HPLC [Daicel Chiralpak AD-H, hexane–i-PrOH (98:2),
flow rate 0.7 mL/min,  = 254 nm, 25 °С]: tR (major) = 9.18 min,
tR (minor) = 11.06 min. 1H NMR (500 MHz, CDCl3):  = 7.86 (s, 1
H), 7.45 (t, J = 7.5 Hz, 1 H), 7.40 (d, J = 7.4 Hz, 1 H), 7.35–7.31 (m,
3 H), 7.18 (t, J = 7.6 Hz, 2 H), 7.12 (d, J = 8.5 Hz, 1 H), 6.89 (d,
J = 8.0 Hz, 2 H), 2.81–2.71 (m, 2 H), 2.69 (s, 3 H), 2.66–2.60 (m, 1
H), 2.58–2.51 (m, 1 H), 2.54 (s, 3 H), 2.07 (s, 3 H). 13C NMR (126
MHz, CDCl3):  = 205.21, 153.48, 147.61, 145.30, 142.95, 140.73,
139.81, 134.64, 134.42, 130.06, 129.38, 129.19, 128.84, 128.56,
127.98, 126.19, 125.66, 125.17, 125.14, 125.11, 125.08, 123.42,
36.13, 34.62, 31.96, 23.85, 21.71. HRMS (Bruker micrOTOF-QII):
m/z [M + H]+ calcd for C28H25F3NO: 448.1883; found: 448.1879.
(16) CCDC 1957624 contains the supplementary crystallographic
data for compound (S,R)-5. The data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E