Silver catalyzed synthesis of 4-trifluoromethyl substituted quinolines in water

Article abstract of DOI:10.1039/c3ra41991f

Herein we report the first silver catalyzed fluorinated quinoline synthesis via a cascade alkyne-ketone-amino coupling/addition/condensation process in water.

Full text of DOI:10.1039/c3ra41991f

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Silver catalyzed synthesis of 4-trifluoromethyl
substituted quinolines in water3
Cite this: DOI: 10.1039/c3ra41991f
Bing-Chuan Zhao,a Qing-Zhou Zhang,a Wen-Yu Zhou,b Hu-Chun Tao*a and Zi-
Gang Li*a
Received 23rd April 2013,
Accepted 5th June 2013
DOI: 10.1039/c3ra41991f
www.rsc.org/advances
Herein we report the first silver catalyzed fluorinated quinoline
synthesis via a cascade alkyne–ketone–amino coupling/addition/
condensation process in water.
good yield, however, it may still have regio-selectivity issues44
(Fig. 2).
Due to fluorinated compounds’ special chemical, physical and
physiological effects,45–48 the chemical community cast significant
interests over them.49–53 The reports of synthesis of 4-trifluor-
omethyl substituted quinolines are rare, stoichiometric amount of
metal salts and organic solvents are necessary with limited
substrate scope.54 Herein, we want to report a facile synthesis of
4-trifluoromethyl substituted quinolines via an aqueous silver-
catalyzed environmentally-friendly tandem process with high atom
economy. The only by-product is one molecule of H2O per
molecule of quinoline product.
This facile tandem process is composited by a propargyl
alcohol synthesis via a sp C–H activation followed by an amine–
alkyne addition and a final condensation to give final quinoline
products.54 The substrate scope can be extended to simple
aliphatic alkynes and avoid using of stoichiometric amount of
metal salts/organic solvents comparing with previous report,
which makes this methodology more applicable in synthesis in
addition to its environmental merits.1–3
We employed o-aminophenyltrifluoroethanones and alkynes as
substrates. After screening different catalysts, we found silver
showed superior catalytic ability when applied together with
phosphine ligands and organic bases. Electron rich phosphine
ligands, such as tricyclohexyl phosphine, show similar accelerating
effect as triphenyl phosphine, while electron deficient phosphines
are significantly less effective. Due to the economical reasons,
triphenyl phosphine is chosen as the ligand for the standard
One of the most important conceptual revolutions of chemistry
research and the chemical industry in the late 20th century is the
increasing attention from the public regarding designing and
developing environmentally-benign chemical processes from the
very beginning.1–10 Collecting and disposal of organic solvents
consume a major section of the chemical industry spending.11
One recent important advance is using less polluting solvents,
such as water,12–18 ionic liquid19–22 and super critical CO2,23–26 as
substitutes for halogen-containing and/or aromatic organic
solvents. Water has superior commercial accessibility over any
other solvents and also shows some special accelerating char-
acteristic in catalysis.27,28 Thus, the need of developing synthesis
methodologies in water becomes increasingly demanding. ‘‘Atom
Economy’’ has also drawn the community’s attention. It plots an
ideal chemical process which converts maximum atoms from the
substrate(s) into the target molecule(s), avoiding by-products
(wastes) by not making them.29,30
Quinolines are important heterocycle cores of various natural
products and commercial drugs, such as quinine,31,32 bucha-
pine,33 2-acetylevolitrine,34 skimmianine,35 aurachin RE36 (Fig. 1).
They are also important building components for organic light-
emitting diodes (OLEDs) and photovoltaic devices.37,38
Traditional approaches towards quinolines such as Skraup,
Doebner–von Miller, and Combes reactions can be applied in
synthesizing simple quinoline derivatives with relatively poor
regioselectivity.39–43 Recent developments of quinoline synth-
esis via Friedlander conditions involve condensation of
2-aminoaryl-ketones with specially prepared b-keto-ester type
substrates. This process could provide substituted quinolines in
aPeking University Shenzhen Graduate School, Shenzhen University Town Peking
University Campus, Shenzhen, Guangdong, 518055, P.R.C..
E-mail: taohc@pkusz.edu.cn; lizg@pkusz.edu.cn; Fax: +86 755-2603-3174
bShenzhen Second People’s Hospital, 3002, ShunGang West Road, Shenzhen,
Guangdong, 518055, P.R.C.
Fig. 1 Representative compounds containing quinoline core.
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra41991f
3
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Table 2 Scope of substratesa
Entry
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
Cl
Cl
Cl
Cl
OMe
OMe
OMe
OMe
CF3
CF3
CF3
CF3
H
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
Ph
n-Bu
cyclopropyl
4-methylphenyl
Ph
3aa
3ab
3ac
3ad
3ba
3bb
3bc
3bd
3ca
3cb
3cc
3cd
3da
3db
3dc
3dd
73b
83
85
80
90
24
48
57
69
60
81
70
38
21
56
37
Fig. 2 Friedlander reaction.
condition. AgF gives higher yields over other silver salts screened
and triethylamine is chosen as the base, solid inorganic bases are
not suitable for this reaction (Table 1).
n-Bu
cyclopropyl
4-methylphenyl
Ph
9
O-Aminophenyltrifluoroethanones bearing both electron
donating or electron withdrawing groups can undergo this
reaction to give corresponding products (Table 2), however,
ketones with electron withdrawing groups like 1a or 1c give
higher yields (Entry 1–4, 9–12), which could be explained by the
higher ketone carbonyl reactivity towards alkynes. In general,
aromatic alkynes 2a and 2d give better yields than aliphatic ones
2b and 2c. Notably, ethynylcyclopropane 2c shows better reactivity
than 1-hexyne 2b, gives moderate to good yields with all ketones
(Entry 3, 7, 11, 15). This retention of cyclopropyl group suggests
this reaction may go through a homogenous metal catalyzed C–H
activation pathway in the step of propargyl alcohol formation,
instead of a radical initiated reaction.
Transition metal catalyzed alkyne addition to normal ketones
is a formidable task to be yet fully conquered, it is also true in our
case.55 Ketones bearing a CF3 group give good to excellent yields
with both aromatic and aliphatic alkynes, normal ketones could
not undergo this reaction, which is still a unsolved task based on
our knowledge. If the amine is protected, we can isolate
corresponding propargyl alcohol 3ea in good yield (Scheme 1).
Thus, we propose the reaction mechanism as: silver catalyst first
10
11
12
13
14
15
16
n-Bu
cyclopropyl
4-methylphenyl
Ph
n-Bu
cyclopropyl
4-methylphenyl
H
H
H
a
All reactions were carried out with 1 (0.2 mmol), 2 (0.6 mmol), AgF
(0.01 mmol), PPh3 (0.01 mmol) and NEt3 (0.4 mmol) in 4 ml water,
isolated yields of 3 were reported. If the reaction was carried out at
2 mmol scale in 5 ml water, 66% 3aa was isolated after 24 h
reaction.
b
activates the sp C–H bond and its addition to ketones to form
propargyl alcohols 7, then the o-amino group adds to alkyne which
followed by a condensation step to give the products and one
molecule H2O as by product (Scheme 2).
During this research, we also find an intriguing transforma-
tion: we propose to use an aldehyde carbonyl group instead of
amine in the nucleophilic addition step, thus we employ 1,2-
dibenzaldehyde 8 as the substrate, two products are identified as
shown in Scheme 3. Interestingly, together with the easily
understandable hemi acetal product, an indenone product is also
identified, which could only form though an unusual addition of
carbonyl C–H bond to alkynes.
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Base
Yield (%)
1
2
3
4
5
6
7
AgF
NEt3
NEt3
NEt3
NEt3
DIPEA
Pyridine
Pyrrolidine
73
43
43
58
48
38
46
AgNO3
Ag2O
AgOAc
AgF
AgF
AgF
a
All reactions were carried out with 1a (0.2 mmol), 2a (0.6 mmol),
AgX (0.01 mmol), PPh3 (0.01 mmol) and base (0.4 mmol) in 4 ml
water, isolated yields of 3aa were reported.
Scheme 1 Propargyl alcohol formation. All reactions were carried out with 1e (0.2
mmol), 2a (0.6 mmol), AgF (0.01 mmol), PPh3 (0.01 mmol) and NEt3 (0.4 mmol),
isolated yield.
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We propose a tentative mechanism for the intriguing indenone
formation as shown in Scheme 3. The first step also goes through
a silver catalyzed sp C–H activation, which results in correspond-
ing propargyl alcohol 11; the hydroxyl group of the newly formed
propargyl alcohol may attack the neighboring carbonyl carbon
center to form hemi acetal 10 or the alkynyl group may react with
the carbonyl C–H bond to afford indenone 9. The role of silver
catalyst in the indenone formation is still illusive, it may go
through either a silver catalyzed alkyne-ketone metathesis inter-
mediate 12 or a silver catalyzed carbonyl C–H activation via
carbene insertion intermediate 13.
Conclusions
Herein we report a facile silver catalyzed 4-trifluoromethyl
substituted quinoline synthesis in water with high atom economy.
It provides new approaches for important quinoline intermediates
bearing CF3 group, this protocol is applicable with both aromatic
and aliphatic alkynes. Further research of this transformations
with normal ketones and the silver catalyzed carbonyl C–H
addition is under current investigations.
Scheme 2 Proposed mechanism of the quinolines synthesis catalyzed by silver in
water.
Experimental
General procedure for production of quinoline derivatives
Due to the intrinsic competition of the facile hemi acetal
formation, the indenone transformation could only give moderate
yield. The hemi acetal product will decompose if we increase the
reaction time to over 12 h, which facilitate the isolation of desired
indenone product. Although at this moment, this transformation
is still limited by scope and efficiency, it implicates a broader
scope of further application of the silver catalyzed alkyne addition
reactions56,57 (Scheme 3).
To a sealed tube equipped with magnetic stir bar and Teflon-seal
screw cap was added 0.2 mmol aniline, 4 ml water, then 0.01
mmol AgF, 0.01 mmol PPh3, 0.6 mmol alkynes and 0.4 mmol NEt3
(66 ml) was added to the mixture in the sealed tube under the
atmosphere of air. The mixture was stirred at the temperature of
120 uC (bath temperature) for 0.5–3 h. After the reaction was
complete, the reaction mixture was extracted with ethyl acetate.
The mixture was concentrated under a reduced pressure. The
residue was purified by flash column chromatography on silica gel
(eluent = hexane–EtOAc 50–100 : 1).
Acknowledgements
We thank the National Natural Science Foundation of China
Grant 21102007, the Shenzhen Science and Technology
Innovation Committee SW201110060 and SW201110018, the
Shenzhen Peacock Program (KQTD201103) to Z.G.L.
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Scheme 3 Indenone formation.
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