Palladium catalyzed synthesis of 2-trifluoromethylquinolines through a domino Sonogashira-alkyne carbocyclization process

Article abstract of DOI:10.1039/b925285a

A new, rapid and high-yielding method to prepare 3,4-disubstituted 2-trifluoromethylquinolines by a palladium catalyzed tandem Sonogashira-alkyne carbocyclization of β-trifluoromethyl β-enaminoketones with arynes is described. Moderate to excellent yields have been achieved under mild conditions. This reaction can also be expanded to the non-fluorine containing substrates. The reaction mechanism is also discussed. The Royal Society of Chemistry.

Full text of DOI:10.1039/b925285a

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Palladium catalyzed synthesis of 2-trifluoromethylquinolines through
a domino Sonogashira–alkyne carbocyclization processw
Zixian Chen,ab Jiangtao Zhu,a Haibo Xie,a Shan Li,a Yongming Wu*a and Yuefa Gong*b
Received (in Cambridge, UK) 1st December 2009, Accepted 3rd February 2010
First published as an Advance Article on the web 25th February 2010
DOI: 10.1039/b925285a
A new, rapid and high-yielding method to prepare 3,4-disubstituted
2-trifluoromethylquinolines by palladium catalyzed tandem
was obtained in 12% yield (Table 1, entry 1). Interestingly,
using Pd(PPh3)2Cl2 alone also produced the target product 3a
in 12% yield (Table 1, entry 2). Encouraged by these results,
different bases were examined. Both Cs2CO3 and K3PO4
(Table 1, entries 3–4) were efficient bases as compared with
DMAP and pyridine (Table 1, entries 5–6). The yield was
improved considerably when DBU was used as the base
(Table 1, entry 7). Other palladium salts, such as Pd(OAc)2
and PdCl2, led to lower yields of the desired molecule (Table 1,
entries 8–9), and no product was observed when CuI was used
as the catalyst. Finally, other solvents such as toluene and
CH3CN were evaluated. Compared with DMF, the reaction in
CH3CN was completed in a shorter time (Table 1, entry 11),
and the amount of DBU used could be reduced to 2.2 equiv.
(Table 1, entry 14). Reducing the catalyst loading to 5 mol%
depressed the yield and prolonged the reaction time (Table 1,
entry 13). After optimization, the best reaction conditions
were ascertained as 10 mol% Pd(PPh3)2Cl2, 2.2 equiv. of
DBU, and 1.5 equiv. of alkynes in MeCN at 60 1C (Table 1,
entry 14). As expected, aryl iodides showed better reactivity
than aryl bromides (Table 1, entry 14 vs. 15), and aryl
chlorides showed no reactivity (Table 1, entry 16).
a
Sonogashira–alkyne carbocyclization of b-trifluoromethyl b-enamino-
ketones with arynes is described. Moderate to excellent yields
have been achieved under mild conditions. This reaction can also
be expanded to the non-fluorine containing substrates. The
reaction mechanism is also discussed.
The quinoline scaffold plays an important role as a component of
antimalarial, antibacterial, antiasthmatic, antihypertensive, and
antiinflammatory agents.1–3 In particular, fluorine-containing
quinolines are of significant interest because fluorine atoms
sometimes play a pivotal role in bioactive compounds, and they
provide a further avenue for structural elaboration.4 For
instance, the antiprotozoal drug mefloquine, which has a
2-trifluoromethylquinoline skeleton, is one of the main agents
for the current treatment of malaria.5
Despite the importance of these heterocycles, their synthetic
routes to fluorinated derivatives are limited. Classical methods
include direct fluorination of a suitable functional group
by nucleophilic or electrophilic fluorinating reagents,6 direct
introduction of fluoroalkyl groups by an Ullmann-type reaction
of perfluoroalkyl iodides with aryl halides using copper powder,7
and acid (or POCl3) catalyzed intramolecular ring closure of the
4-anilino-1,1,1-trifluorobut-3-en-2-ones.4e,8 Recently, transition
metal catalyzed synthesis of 2-trifluoromethylquinolines was also
reported.9 All of these approaches suffer from the limited
availability of the starting materials to poor yields and regio-
selectivity. Herein, we report a one-step and high-yielding
procedure to synthesize 3,4-disubstituted 2-trifluoromethyl-
quinolines from b-trifluoromethyl b-enaminoketones.
As listed in Table 1, 4,4,4-trifluoro-3-(2-iodophenylamino)-
1-phenylbut-2-en-1one 1a and phenylacetylene 2a were chosen
as the model substrates to screen the optimal reaction
conditions. Initial experiments were performed using 1.5 equiv.
of phenylacetylene 2a, and 4 equiv. of Et3N, in the presence
of 5 mol% of Pd(PPh3)2Cl2 and 10 mol% of CuI as the
catalysts, in DMF at 60 1C under a nitrogen atmosphere
overnight. The desired 2-trifluoromethylquinoline product 3a
To investigate the scope of the proposed synthetic strategy,
which includes two C–C bond-forming steps, a number of
b-trifluoromethyl b-enaminoketones, which could be prepared
from the condensation of simple reagents of methyl ketones
with trifluoroacetimidoyl chlorides in high yields,10 were tested.
As displayed in Table 2, when R2 was an aromatic ring with an
electron-donating group, the products were isolated in good
yields (Table 2, entries 1–3). In contrast, when R2 was an
aromatic ring with an electron-withdrawing group or alkyl group,
lower yields were obtained (Table 2, entries 4–6). Conversely, if
R1 was an electron-withdrawing group, the reaction was com-
plete in a shorter time as compared with electron-donating
groups (Table 2, entries 8–11). Interestingly, when 3-(5-chloro-
2-iodophenylamino)-4,4,4-trifluoro-1-phenylbut-2-en-1-one (1m)
was used as the substrate, only 3-(5-chloro-2-(phenylethynyl)-
phenylamino)-4,4,4-trifluoro-1-phenylbut-2-en-1-one 3m was
obtained, which did not undergo further cyclization even in the
presence of stronger bases, such as MeONa, t-BuOK (Table 2,
entry 12). However, substrates with R1 as a strongly electron-
withdrawing NO2 group at the para position provided an
intramolecular C–O bond formation product 7-nitro-2-phenyl-
4-(trifluoromethyl)benzo[b][1,4]oxazepine 4n via aromatic nucleo-
philic substitution (Table 2, entry 13), without forming the target
quinoline ring. It was of interest to find that when the CF3 group
was replaced by CF2Cl in b-fluoromethyl b-enaminoketone 1,
only the starting material was recovered. N-(2,2-difluoro-5-phenyl-
furan-3(2H)-ylidene)-2-iodoaniline was obtained through a
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China. E-mail: ymwu@mail.sioc.ac.cn;
Fax: (+86) 21-54925192
b School of Chemistry and Chemical Engineering, Huazhong
University of Science and Technology, Wuhan, Hubei 430074, China.
E-mail: gongyf@mail.hust.edu.cn
w Electronic supplementary information (ESI) available: Detailed
synthetic procedures and analytical data for new compounds. See
DOI: 10.1039/b925285a
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Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Base
Solvent
Time/h
Conversion (%)b
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2(5%)/CuI(10%)
Pd(PPh3)2Cl2(5%)
Pd(PPh3)2Cl2(10%)
Pd(PPh3)2Cl2(10%)
Pd(PPh3)2Cl2(10%)
Pd(PPh3)2Cl2(10%)
Pd(PPh3)2Cl2(10%)
Pd(OAc)2(10%)
Et3N
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Overnight
’’
’’
’’
’’
’’
’’
’’
’’
’’
2
4
12
2
12(10)
12(10)
78
59
—
CsCO3
K3PO4
DMAP
Pyridine
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
—
99(97)
46
73
—
99
9
PdCl2(10%)
CuI (10%)
DMF
DMF
10
11
12
13
14
15
16
Pd(PPh3)2Cl2(10%)
Pd(PPh3)2Cl2(10%)
Pd(PPh3)2Cl2(5%)
Pd(PPh3)2Cl2(10%)
Pd(PPh3)2Cl2(10%)
Pd(PPh3)2Cl2(10%)
CH3CN
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
95
92
98c,d
45d,e
24
24
d,f
—
a
Reactions were carried out on a 0.2 mmol scale in DMF (2 mL) under nitrogen at 60 1C overnight with alkyne (2 equiv.) and base (4 equiv.)
unless otherwise stated. Reported yields were based on 1a. Determined by 19F NMR. Values in parentheses are of isolated yield. Alkyne
d
(1.5 equiv.) was used. DBU (2.2 equiv.) was used. X = Br. X = Cl.
b
c
e
f
Table 2 Reactions of various b-enaminoketones with phenylacetylenea
structure may have
effect.12–13
a strong ortho-substituent chelating
The scope of the intermolecular cyclization reaction was
further expanded to a variety of terminal alkynes (Table 3).
Yields for all reactions were good to excellent (84–98%).
Arylacetylenes bearing electron-withdrawing substituents gave
higher yields and required shorter times than those bearing
electron-donating substituents (Table 3, entries 1–4). All
para-, meta-, and ortho-substituted phenylacetylenes and
2-ethynylnaphthalene were smoothly transformed into the
desired products, which indicated that steric bulk did not
significantly affect the reactivity (Table 3, entries 6–7). The
cascade processes all occurred with good yields, even the terminal
alkyne possessing a heterocyclic ring (Table 3, entries 8–9).
Entry
R
R1
R2
Product Time/h Yield (%)b
1
2
3
4
5
6
7
8
CF3
CF3
CF3
CF3
CF3
CF3 4-Me
CF3 4-F
CF3 4-Me
CF3 4-F
CF3 4-CF3 Ph
CF3 5-MeO Ph
CF3 5-Cl
CF3 5-NO2 Ph
Ph Ph
H
H
H
H
H
4-MeOC6H4 3b
3-MeOC6H4 3c
2-Furyl
Cyclopropyl 3e
Me
4-ClC6H4
2-Naphthyl 3h
2
4
2
4
3
3
3
4
2
1
3
2
2
5 d
91
95
91
73
77
86
85
90
89
93
86
85
75
75c
3d
3f
3g
Ph
Ph
3i
3j
9
Table 3 Reactions of 1a with representative arynesa
10
11
12
13
14
3k
3l
3m
4n
3o
Ph
H
a
Reactions were carried out on a 0.5 mmol scale in CH3CN (2 mL)
under nitrogen at 60 1C with catalyst (10 mol%), alkyne (1.5 equiv.)
and base (2.2 equiv.) unless otherwise stated. Isolated yields.
b
Entry
R3
Product
Time/h
Yield (%)b
c
Reaction occurred at 80 1C.
1
2
3
4
5
6
7
8
9
4-Cl–C6H4
4-OMe–C6H4
4-F–C6H4
4-Me–C6H4
3-OMe–C6H4
2-Cl–C6H4
2-Naphthyl
2-Thienyl
3p
3q
3r
3s
3t
3u
3v
3w
3x
1
2
1
2
1
2
2
1
1
98
84
96
91
95
94
94
93
93
halophilic process when the CF3 group was replaced by
CF2Br.11 Surprisingly, when the CF3 group of b-trifluoromethyl
b-enaminoketone 1 was replaced by a phenyl group, the
quinoline ring was also formed in satisfactory yield, although
a longer reaction time (5 days) and higher temperature
were required (Table 2, entry 14). However, when the CF3
group of b-trifluoromethyl b-enaminoketone 1 was replaced by
an alkyl group (e.g. methyl), no desired product could be
obtained. These results indicate that the NHC(CF3)QCHCOR
2-Pyridyl
a
Reactions were carried out on a 0.5 mmol scale in CH3CN (2 mL)
under nitrogen at 60 1C with catalyst (10 mol%), alkyne (1.5 equiv.)
and base (2.2 equiv.) unless otherwise stated. Isolated yields.
b
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Scheme 1 Proposed mechanism.
However, aliphatic terminal alkynes, such as 1-hexyne, did not
give the desired product under the standard conditions.
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(b) D. Dube, M. Blouin, C. Brideau, C. Chan, S. Desmarais,
D. Ethier, J. Falgueyret, R. W. Friesen, M. Girard, Y. Girard,
J. Guay, D. Riendeau, P. Tagari and R. N. Young, Bioorg. Med.
Chem. Lett., 1998, 8, 1255–1260.
´
A possible mechanism of this transformation is proposed in
Scheme 1.14 The first step is the oxidative addition of Pd(0)
with aryl halide. The presence of an ortho-b-acyl-enamine
group as a ligand makes this step easier (I). Coordination of
the alkyne to the ArPdOR complex then followed. Because no
copper salt is employed, and the bases are not strong enough
to abstract a proton from the alkyne, a transmetalation step
may be excluded. The terminal alkyne C–H bond activation is
accomplished by the coordination of the alkyne to the
ArPdOR complex. Upon coordination, the C–H bond is
weakened, and HOR is removed from Pd(II) in the presence
of a base to form an arylalkynylpalladium species III, which
undergoes reductive elimination to afford the product IV
regenerating the catalyst. Product IV then undergoes a base
catalyzed alkyne carbocyclization15 process to afford V, which
then isomerizes to the target compound 3.
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J. Org. Chem., 1999, 937–941; (b) B. Crousse, J. Begue and
D. Bonnet-Delpon, J. Org. Chem., 2000, 65, 5009–5013;
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Chem., 1994, 59, 607–615; (e) M. Schlosser, H. Keller, S. Sumida
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31, 2689–2692; (b) H. Keller and M. Schlosser, Tetrahedron, 1996,
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In conclusion, we have designed a new, rapid, and high-yielding
synthetic approach to 3,4-disubstituted 2-trifluoromethylquino-
lines via a tandem Sonogashira–alkyne carbocyclization process
under extremely mild conditions, in which two new C–C bonds
are formed during a one-pot procedure, and it works well
with non-fluorine containing substrates. In addition, the
NHC(CF3)QCHCOR structure has a strong ortho-substituent
chelating effect on the Sonogashira C–C bond formation process.
This work was supported by the National Science Founda-
tion of China (Nos. 20532040 and 20772145).
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Chem. Commun., 2010, 46, 2145–2147 | 2147