Synthesis of 3-alkyl-1H-quinolin-2-ones via palladium-catalyzed intramolecular cyclization of benzyl halides and α,β-unsaturated amides

Article abstract of DOI:10.1055/s-2008-1077875

An efficient synthesis of 3-alkyl-1H-quinolin-2-ones was achieved in high yield (up to 91%) via Pd₂(dba)₃-catalyzed intramolecular cyclization of benzyl halides and electron-deficient olefins, followed by treatment with DBU. Thieme S

Full text of DOI:10.1055/s-2008-1077875

1734
LETTER
Synthesis of 3-Alkyl-1H-quinolin-2-ones via Palladium-Catalyzed
Intramolecular Cyclization of Benzyl Halides and a,b-Unsaturated Amides
S
ynthesis of 3-A
h
lkyl-1
H
-qu
a
ns
gqin Liu,a,b Changqing Shi,a,b Yuanwei Chen*a
a
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Fax +86(28)85232228; E-mail: chenyw@cioc.ac.cn
b
Graduate School, Chinese Academy of Sciences, Beijing 100039, P. R. of China
Received 1 March 2008
(1a,8 Scheme 1). The reaction was initially performed in
refluxing MeCN for 12 hours with Pd(PPh3)4 (5% mol)
and 3 equivalents of Et3N. Besides the expected 3-alkyl-
1H-quinolin-2-one was obtained, another three cycliza-
tion products 3a–c were also isolated. Compounds 3a and
3c are the acetylated products of 3b and 2a, respectively.
By treatment of the reaction mixture with DBU, 3a–c
were successfully converted to 3-methyl-1H-quinolin-2-
one (2a) as a single product in moderate yield (67%).9
Abstract: An efficient synthesis of 3-alkyl-1H-quinolin-2-ones
was achieved in high yield (up to 91%) via Pd2(dba)3-catalyzed in-
tramolecular cyclization of benzyl halides and electron-deficient
olefins, followed by treatment with DBU.
Key words: palladium, cyclization, benzyl halides, electron-defi-
cient olefins, quinolinone
Since modern palladium chemistry started in 1960, palla-
dium catalysts have received considerable attention be-
cause of their wide applications in carbon–carbon bond
formations such as Heck reaction,1 Sonogashira cou-
pling,2 and Suzuki coupling.3 However, palladium-cata-
lyzed coupling of benzyl halides and olefins have not been
studied extensively. Negishi’s group first reported the in-
tramolecular cyclization of benzyl halides and unfunc-
tionalized olefins to form five- to seven-membered rings.4
Several other groups also reported the cyclization of ben-
zyl halides and simple olefins or electron-rich olefins.5
However, as far as we are aware of, there are no further
studies on the cyclization of benzyl halides and electron-
deficient olefins. Here, we report the first synthesis of 3-
alkyl-1H-quinolin-2-ones via palladium-catalyzed in-
tramolecular cyclization of benzyl halides and electron-
deficient olefins. The 3-alkyl-1H-quinolin-2-one moiety
is present in a number of biologically active compounds
such as R207910 (Figure 1), which has been described to
have significant activity against drug-sensitive and drug-
resistant Mycobacterium tuberculosis6 and elicit antitu-
bercular activity.7
Br
N
+
N
O
O
N
H
O
O
O
O
Pd(PPh3)4
3b 16%
3a 21%
Et3N, MeCN
+
N
1a
N
H
O
O
2a 20%
3c 11%
67%
DBU
N
H
O
2a
Scheme 1 Palladium-catalyzed cyclization of N-acetyl-N-[2-(bro-
mo-methyl)phenyl]acrylamide (1a) to yield 3-methyl-1H-quinolin-2-
one (2a)
In search of the optimized reaction conditions, we began
our initial study by examining the intramolecular cycliza-
tion of N-acetyl-N-[2-(bromomethyl)phenyl]acrylamide
Encouraged by the successful intramolecular cyclization
of acrylamide 1a, we further investigated a variety of
ligands to promote the reaction (Table 1, entries 1–9). To
our surprise, the combination of Pd2(dba)3 and dppf or L2
dramatically increased the yield of 2a to 91% and 90%,
respectively (entries 3 and 9). Other ligands such as L1,
L3,10 dppm, dppe, dppb, and Xantphos (entries 2, 4–8)
gave moderate yields after longer reaction time. Inorganic
bases, such as K2CO3, Na2CO3, Cs2CO3, and organic
bases such as DABCO and DBU were found to provide no
products for this reaction (entries 10–14). In nonpolar sol-
vents such as toluene (entry 15), no cyclization products
could be isolated and the starting material 1a was quanti-
tatively recovered. In apolar solvents other than MeCN,
poor or moderate yields were obtained (entries 16–19).
OH
Br
NMe2
N
O
Me
Figure 1 Structure of R207910
SYNLETT 2008, No. 11, pp 1734–1736
x
x
.x
x
.2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1077875; Art ID: W03508ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Alkyl-1H-quinolin-2-ones
1735
Table 1 Optimization of the Pd-Catalyzed Cyclization Reactiona
used (entry 2). A number of 3-aryl acrylamides were also
examined.
Br
The phenyl ring can be substituted at the 3- or 4-position,
and the group can be electron-donating or electron-with-
drawing (entries 4–8).13 When heterocyclic acrylamide
substrate was employed, the corresponding cyclization
product was also obtained in 71% yield (entry 10). How-
ever, the cyclization did not happen with the 2-nitrophe-
nyl acrylamide substrate (entry 9), probably due to steric
hindrance. 3-Alkyl substitution on acrylamide (entry 11)
could also give the desired cyclization product 2h, though
in a lower yield. Methyl substitution on benzene ring also
cyclized smoothly to give the corresponding products in
moderate yield (entries 12 and 13).
O
O
cat. Pd2(dba)3 (2.5 mol%)/L
DBU
reflux
base, solvent, reflux
N
N
O
H
2a
1a
P(t-Bu)2
PCy2
P(t-Bu)2
Me2N
L3
L1
L2
Entry Ligand
Base
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
Time (h) Yield (%)b
Table 2 Synthesis of 2-Hydroxyquinolines
1c
2
(PPh3)4
L1
15
30
12
30
30
18
30
18
8
67
X
R1
R2
66
R2
Pd2(dba)3 (2.5 mol%)
dppf (5 mol%)
R1
OH
DBU
reflux
3
L2
90
Et N, MeCN, reflux
3
N
O
N
4
L3
43
1
2
O
5
dppm
dppe
52
Entry
X
R1
R2
Yield of 2 (%)a
91 (2a)
n.r.
6
71
1
2
3
4
5
6
7
8
9
Br
AcO
Cl
H
H
H
H
H
H
H
H
H
H
7
Xantphos Et3N
36
H
8
dppb
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
dppf
Et3N
73
H
67 (2a)
73 (2b)b
85 (2c)
76 (2d)b
81 (2e)
66 (2f)b
n.r.
9
Et3N
91
Br
Br
Br
Br
Br
Br
Ph
10d
11d
12d
13e
14e
15
16
17
18
19
K2CO3
Na2CO3
Cs2CO3
DABCO
DBU
3
NR
NR
NR
NR
NR
Trace
Trace
36
3-O2NC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-O2NC6H4
3
3
3
3
Et3N
30
O
10
Br
H
H
71 (2g)
Et3N
1,4-Dioxane 32
O
Et3N
THF
30
12
15
11
12
13
Br
Br
Br
Me
36 (2h)
61 (2i)
65 (2j)
Et3N
DMF
DMSO
51
H
Me
Me
Et3N
49
Ph
a Conditions: 1a (1.0 equiv), Et3N (3 equiv), Pd2(dba)3 (2.5 mol%),
diphosphine ligand (5 mol%) or monophosphine ligand (10 mol%),
solvent (5 mL).
a Yield of isolated product.
b See ref.11 for structural confirmation.
b Yield of isolated product.
c Pd(PPh3)4 instead of Pd2(dba)3 and ligand was used.
d Starting material was completely destroyed by the inorganic base.
e Starting material disappeared without cyclization products.
In summary we have developed a novel practical ap-
proach to synthesize 3-alkyl-1H-quinolin-2-ones via the
cyclization of benzyl halides with a,b-unsaturated amides
promoted by Pd2(dba)3 and dppf as catalysts. Further stud-
ies to expand the scope of reaction are in progress.
This novel palladium-catalyzed intramolecular cycliza-
tion can be applied to a wide range of acrylamide
(Table 2). In addition to the benzyl bromides,12 benzyl
chloride could be employed to give the cyclization prod-
uct 2a in 67% yield (entry 3). But the cyclization reaction
failed with benzyl acetate even when more catalysts were
Acknowledgment
We would like to thank 100 talents program of Chinese Academy
of Sciences, the Chengdu Institute of Organic Chemistry, and Gra-
Synlett 2008, No. 11, 1734–1736 © Thieme Stuttgart · New York

1736
Z. Liu et al.
LETTER
Flash chromatography (EtOAc–light PE = 20:80) of the
duate School of Chinese Academy of Science for financial support
of this work.
residue gave N-[2-(hydroxymethyl)phenyl]acrylamide (1.45
g, 8.19 mmol) in 81.9% yield as a white solid. Then, PBr3
(1 equiv) was dropped slowly to the solution of N-[2-(hy-
droxymethyl)phenyl]acrylamide in CH2Cl2 at 0 °C and
stirred for 30 min. The reaction mixture was quenched with
H2O, and the aqueous layer was extracted with additional
CH2Cl2, and the combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. The residue was
purified by flash chromatography on SiO2 by using 10%
EtOAc–light PE as eluent to give N-[2-(bromometh-
yl)phenyl]acrylamide in 73% yield as a white solid. Then
acetyl chloride (3 equiv) was added to N-[2-(bromo-
methyl)phenyl]acrylamide (5 mmol, 1.195 g) and CaH2 (3
equiv), and stirred in dry THF for 24 h. The reaction mixture
was filtered and the filtrate was concentrated in vacuo. The
residue was purified by flash chromatography on SiO2 by
using 8% EtOAc–light PE as eluent to give acrylamide
N-acetyl-N-[2-(bromomethyl)phenyl]acrylamide in 90%
yield as a white solid.
References and Notes
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P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
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2001, 42, 203. (f) Haeberli, A.; Leumann, C. J. Org. Lett.
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(2) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467. (b) Hundermark, T.; Littke, A.;
Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729.
(c) Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4,
1411. (d) Balova, I. A.; Morozkina, S. N.; Knight, D. W.;
Vasilevsky, S. F. Tetrahedron Lett. 2003, 44, 107.
(3) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Stanforth, S. P. Tetrahedron 1998, 54, 263. (c) Urawa,
Y.; Ogura, K. Tetrahedron Lett. 2003, 44, 271.
(4) (a) Wu, G.; Lamaty, F.; Negishi, E. J. Org. Chem. 1989, 54,
2507. (b) Wu, G.; Shimoyama, I.; Negishi, E. J. Org. Chem.
1991, 56, 6506.
(5) (a) Pan, Y.; Zhang, Z. Y.; Hu, H. W. Synthesis 1995, 245.
(b) Hu, Y. M.; Zhou, J.; Lian, H. Z.; Zhu, C. J.; Pan, Y.
Synthesis 2003, 8, 1177. (c) Hu, Y. M.; Zhou, J.; Long, X.
T.; Han, J. L.; Zhu, C. J.; Pan, Y. Tetrahedron Lett. 2003, 44,
5009. (d) Wang, L. S.; Pan, Y.; Jiang, X.; Hu, H. W.
Tetrahedron Lett. 2000, 41, 725.
(9) Acetyl protection of acrylamide 1a is necessary to increase
its activity.
(10) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolf, J. P.;
Sandighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 4369.
(11) Lee, C. G.; Lee, K. Y.; Lee, S. K.; Kim, J. N. Tetrahedron
2005, 61, 1493.
(12) Typical Procedure for the Cyclization of N-Acetyl-N-[2-
(bromomethyl)phenyl]acrylamide
Under the nitrogen atmosphere, the mixture of acrylamide
derivative N-acetyl-N-[2-(bromomethyl)phenyl]acrylamide
(1 mmol, 0.281 mg), Pd2(dba)3 (2.5 mol%), dppf (5 mol%),
and Et3N (3.0 equiv) was stirred in 5 mL refluxing MeCN for
5 h. Then, DBU (1 equiv) was added and the reaction
mixture was refluxed for an additional 3 h. Solvent was
removed and the residue was purified by flash
(6) (a) Cole, S. T.; Alzari, P. M. Science 2005, 307, 214.
(b) Rubin, E. J. N. Engl. J. Med. 2005, 352, 933. (c) Ji, B.;
Jarlier, V. Antimicrob. Agents Chemother. 2006, 50, 1558.
(7) Andries, K.; Verhasselt, P.; Guillemont, J.; Gohlmann, H.
W. H.; Neefs, J.-M.; Winkler, H.; Gestel, J. V.; Timmerman,
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chromatography on SiO2 by using 20% EtOAc–light PE as
eluent to give 2a in 91% yield as a white solid.
(13) Analytical Data of 3-(3-Nitrobenzyl)quinolin-2(1H)-one
(2c)
(8) Typical Procedure for the Synthesis of N-Acetyl-N-
[2-(bromomethyl)phenyl]acrylamide (1a)
Rf = 0.25 (25% EtOAc–light PE); mp 206–209 °C. 1H NMR
(300 MHz, CDCl3): d = 12.27 (s, 1 H, NH), 8.29 (s, 1 H,
ArH), 8.10–8.07 (d, 1 H, ArH), 7.73–7.70 (d, 1 H, ArH),
7.63 (s, 1 H, ArH), 7.52–7.44 (m, 3 H, ArH), 7.32–7.19 (m,
2 H, ArH), 4.10 (s, 2 H, CH2). 13C NMR (300 MHz, CDCl3):
d = 163.8, 148.3, 141.5, 138.2, 137.8, 135.4, 131.6, 130.2,
129.3, 127.4, 124.2, 122.8, 121.6, 119.9, 115.7, 36.4. ESI-
MS: m/z calcd for C16H12N2O3: 280.0848; found: 281.0921
[M + H].
Acryloyl chloride (0.99 g, 11 mmol) was dropped slowly to
the mixture of 2-[(trimethylsilyloxy)methyl]benzamine
(1.95 g, 10 mmol) and 1 equiv Et3N in CH2Cl2 at 0 °C. After
the reaction was complete, the solvent was removed, and the
white solid was dissolved in MeOH, and then K2CO3 (2
equiv) was added. The reaction mixture was stirred for
additional 2 h at r.t. and concentrated. The residue was
dissolved in EtOAc and washed with H2O. The organic
extracts were dried (Na2SO4) and concentrated in vacuo.
Synlett 2008, No. 11, 1734–1736 © Thieme Stuttgart · New York